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Controlled drug delivery vehicles for cancer treatment and their performance

Controlled drug delivery vehicles for cancer treatment and their performance Signal Transduction and Targeted Therapy www.nature.com/sigtrans REVIEW ARTICLE OPEN Controlled drug delivery vehicles for cancer treatment and their performance 1 1 1 1 Sudipta Senapati , Arun Kumar Mahanta , Sunil Kumar and Pralay Maiti Although conventional chemotherapy has been successful to some extent, the main drawbacks of chemotherapy are its poor bioavailability, high-dose requirements, adverse side effects, low therapeutic indices, development of multiple drug resistance, and non-specific targeting. The main aim in the development of drug delivery vehicles is to successfully address these delivery-related problems and carry drugs to the desired sites of therapeutic action while reducing adverse side effects. In this review, we will discuss the different types of materials used as delivery vehicles for chemotherapeutic agents and their structural characteristics that improve the therapeutic efficacy of their drugs and will describe recent scientific advances in the area of chemotherapy, emphasizing challenges in cancer treatments. Signal Transduction and Targeted Therapy (2018) 3:7 https://doi.org/10.1038/s41392-017-0004-3 INTRODUCTION to address some of these challenges by improving treatment Cancer includes a range of diseases that arise as a result of the efficacy while avoiding toxicity in normal cells due to features unregulated growth of malignant cells, which have the potential such as high selective accumulation in tumors via the enhanced to invade or spread to other body parts. With more than 10 million permeability and retention (EPR) effect and active cellular 12,13 new cases each year, cancer-related deaths are projected to uptake . Active targeting approaches may be achieved by increase in the near future with an estimation by the World Health conjugating nanocarriers containing chemotherapeutics to mole- Organization of ~13.1 million cancer-related deaths by the year cules that bind to over expressed antigens. Among emergent 2030 . However, the mortality rate has decreased in the past 5 nanoscale drug carriers, liposomes, polymeric nanoparticles, and years due to a better understanding of tumor biology and micelles have demonstrated great potential clinical impacts. At improved diagnostic devices and treatments. Current cancer present, several nanoparticle-based chemotherapeutics are clini- treatment options include surgical intervention, chemotherapy, cally approved and many more are in various stages of clinical or and radiation therapy or a combination of these options. preclinical development. Although nanocarriers offer many Conventional chemotherapy works primarily by interfering with advantages as drug carrier systems, their lack of biodegradation, DNA synthesis and mitosis, leading to the death of rapidly poor bioavailability, instability in the circulation, inadequate tissue growing and dividing cancer cells. The agents are nonselective distribution and potential toxicity raise concerns over their safety, and can also damage healthy normal tissues, causing severe especially for long-term administration. Cancer chemoresistance, unintended and undesirable side effects, e.g., loss of appetite and which is accountable for most failure cases in cancer therapy, is a nausea. In fact, the severe adverse effects induced by chemother- phenomenon in which cancer cells that are initially suppressed by apeutic drugs on healthy tissues and organs are a major reason an anticancer drug develop resistance towards the particular drug. behind the high mortality rate of cancer patients. Additionally, as For this reason, novel drug delivery systems with better targeting the bio-accessibility of these drugs to tumor tissues is relatively ability are needed for cancer prevention, the suppression of poor, higher doses are required, leading to elevated toxicity in adverse side effects and pain management associated with cancer normal cells and an increased incidence of multiple drug chemotherapy. resistance. Therefore, it is desirable to develop chemotherapeutics In this review article, we discuss various drug delivery vehicles that can either passively or actively target cancerous cells, thereby used in cancer therapeutics to increase the therapeutic index of reducing adverse side effects while improving therapeutic chemotherapeutic drugs. The performance of basic research to efficacy. In the last few years, a better understanding of tumor clinical studies in the context of present day oncological biology and increased availability of versatile materials, including development is discussed. This review presents current challenges 2–5 6,7 8 9,10 polymers , lipids , inorganic carriers , polymeric hydrogels , associated with chemotherapy, followed by a discussion about the and biomacromolecular scaffolds , have led to the development future directions of chemotherapy. of systems that can deliver chemotherapeutics to tumor sites with improved therapeutic efficacy. The emergence of nanotechnology has had a profound impact on clinical therapeutics in general in MATERIALS AND STRATEGIES USED IN CANCER THERAPY last two decades. Compared to conventional chemotherapeutic Several innovative methods of drug delivery are being used in agents, nanoscale drug carriers have demonstrated the potential cancer treatment. A wide range of nanoscale compounds based School of Materials Science and Technology, Indian Institute of Technology (Banaras Hindu University), Varanasi, India Correspondence: Pralay Maiti (pmaiti.mst@itbhu.ac.in) Received: 31 May 2017 Revised: 16 November 2017 Accepted: 6 December 2017 Drug Delivery Vehicles for Cancer Treatment Senapati et al. Scheme 1 Different types of nanocarriers used as controlled delivery vehicles for cancer treatment on synthetic polymers, proteins, lipids, and organic and inorganic Inorganic nanocarriers. Inorganic nanocarrier platforms have particles have been employed for the development of cancer been intensively investigated for therapeutic and imaging therapeutics. Compared with the direct administration of bare treatments in recent years due to their great advantages, such chemo-drugs, drug encapsulation in a carrier offers a number of as large surface area, better drug loading capacity, better advantages, such as protection from degradation in the blood- bioavailability, lower toxic side effects and controlled drug release, stream, better drug solubility, enhanced drug stability, targeted and their tolerance towards most organic solvents, unlike drug delivery, decreased toxic side effects and improved polymer-based nanoparticles. Quantum dots, carbon nanotubes, pharmacokinetic and pharmacodynamic drug properties. To date, layered double hydroxides, mesoporous silica and magnetic an impressive library of various drug delivery vehicles has been nanoparticles are commonly used in cancer treatment in various developed with varying sizes, architectures, and surface physico- ways. Quantum dots have already been proven to be powerful chemical properties with targeting strategies (Scheme 1). Table 1 imaging probes, especially for long-term, multiplexed and 14–16 summarizes some examples of drug delivery systems that have quantitative imaging and diagnostics . Zero dimensional (0- either been approved or are in clinical or preclinical development D) fluorescent nanoparticles, such as quantum dots (QDs) within stages. the size of 1–10 nm, have emerged as one of the most promising nanoparticles for targeted and traceable drug delivery systems, Nanocarriers for drug delivery real-time monitoring of intracellular processes and in vivo Nanomedicine is a rapidly developing area that is molecular imaging due to their unique physicochemical proper- revolutionizing cancer diagnosis and therapy. Nanoparticles ties, such as uniform size, large surface-to-volume ratio, biocom- have unique biological properties given their small size patibility, highly tunable photoluminescence property, improved (diameter within 1–100 nm) and large surface area to signal brightness, resistance against photobleaching and multi- volume ratio, which allows them to bind, absorb and color fluorescence imaging and detection . However, the main carryanticancer agents, such as drugs, DNA, RNA, and challenge with QDs in biological applications is their hydrophobic proteins, along with imaging agents with high efficiency. nature, high tendency of aggregation and non-specific adsorp- 18,19 Nanocarriers used in chemotherapy can be classified into two tion . QD surfaces are usually coated with polar species and/or major types designed for targeted or non-targeted drug delivery: monolayer or multilayer ligand shells to make them water soluble vehicles that use organic molecules as a major building block and to enhance their bioactivity . This type of coating also helps material and those that use inorganic elements (usually metals) as in the development of multifunctional QDs, where imaging a core. Organic nanocarriers are comprised of liposomes, lipids, contrast agents and small molecular hydrophobic drugs can be dendrimers, carbon nanotubes, emulsions, and synthetic embedded between the inorganic core and the amphiphilic polymers. polymer coating layer while hydrophilic therapeutic agents Signal Transduction and Targeted Therapy (2018) 3:7 1234567890();,: Drug Delivery Vehicles for Cancer Treatment Senapati et al. Signal Transduction and Targeted Therapy (2018) 3:7 Table 1. Various drug delivery carriers used in cancer therapy Material Description of Carrier Commercial Name Material Advantage Specificity Ref Carbon nanotube Anti-P-glycoprotein antibody functionalized Overcomes multidrug resistance Human leukemia cells (K562) 191 CNT-doxorubicin Layered double hydroxide Co-delivery of 5-fluorouracil and siRNAs Overcomes drug resistance and enhances cancer Tested on three different cancer 38 (LDH) treatment cell lines Raloxifene intercalated into the interlayer Enhanced therapeutic efficacy; reduction of adverse side Solid tumor 33 gallery of LDH host effects, pure drug Iron oxide nanoparticles Phospholipid-PEG coated superparamagnetic Nano Therm Both chemotherapy and hyperthermia treatment Solid cancer 192 iron oxide nanoparticles Mesoporous silica Azobenzene-modified mesoporous silica for Drug release rate can be controlled by varying the intensity Solid tumor 193 nanoparticles (MSN) NIR-triggered anticancer drug delivery and/or time Endosomal pH-sensitive MSN for doxorubicin Enhances chemotherapeutic efficacy and overcomes Solid tumor 194 delivery multidrug resistance Polymeric nanoparticles Cyclodextrin-PEG nanoparticles covalently CRLX101 Specifically delivers anticancer agents to tumor tissues and Lung and ovarian cancer 195 conjugated with camptothecin reduces side effects PEG-PLGA nanoparticle formulation of BIND-014 Controlled biodistribution, targeted and preferential tumor Various solid malignancies 196 docetaxel accumulation result in increased efficacy and decreased toxicity Liposomes Liposomal doxorubicin Doxil Improved delivery to site of disease; decrease in systemic Karposi’s sarcoma; Ovarian 197 toxicity of free drug cancer; multiple myeloma Liposomal cytarabine Myocet Increased delivery to tumor site; lower systemic toxicity Intrathecal lymphomatous 198 arising from side effects meningitis Liposomal daunorubicin DaunoXome Enhanced delivery to tumor site; lower systemic toxicity Karposi’s sarcoma 199 arising from side effects Micelle Polymeric methoxy-PEG-poly(D,L-lactide) Genexol-PM Improved delivery to site of disease; decrease in systemic Breast cancer; lung cancer; 200 micelle formulation of paclitaxel toxicity of free drug. ovarian cancer PEG-b-poly(α,β-aspartic acid) nanoparticle NK 105 Enhanced antitumor efficacy and dramatically lower Gastric cancer; breast cancer 201 formulation of paclitaxel neurotoxicity than free paclitaxel Protein nanoparticles Human serum albumin-bound paclitaxel Abraxane Improved solubility; improved delivery to tumor Metastatic breast cancer 202 nanoparticles Folate-conjugated bovine serum albumin- Increased solubility, cellular uptake; targeted specifically to Human prostate cancer cells 82 bound paclitaxel nanoparticles cancer cells (PC3) Dendrimer Carboxylated PAMAM dendrimers covalently Improved loading efficiency, reduced cytotoxicity; Lung cancer cells (NCI-H460) 203 conjugated with cisplatin significant anti-proliferative activity against lung cancer Complexation of doxorubicin with cationic Significant increment in therapeutic efficacy of the drug Solid tumor 204 poly-L-lysine dendrimer upon complexation both in vitro and in vivo Drug Delivery Vehicles for Cancer Treatment Senapati et al. (hydrophilic drug, small interfering RNA (siRNA), etc.) and Among the inorganic nanocarriers, two-dimensional (2D) targeting biomolecules (antibodies, proteins, peptides, and layered double hydroxides (LDHs), also known as hydrotalcite- aptamers) can be immobilized onto the hydrophilic side of the like compounds, have recently attracted a great deal of interest for 21,22 23 amphiphiles . Gao et al. developed polymer encapsulated their potential as delivery carriers mainly because of their and bioconjugated QD probes for cancer targeting and in vivo excellent biocompatibility, anion exchange capability, high drug imaging. d-α-Tocopheryl polyethylene glycol 1000 succinate loading efficacy, full protection for loaded drugs, pH-responsive mono-ester (TPGS) coated multifunctional (theranostic) liposomes drug release, ease of preparation, low cost, easy, and efficient have been developed in the form of docetaxel and QD for cancer- penetration into the cell membrane and considerable drug imaging and targeted therapy . Recently, multifunctional QDs delivery, biodegradation in the cellular cytoplasm (pH between have been synthesized, making them a promising targeted drug 4 and 6), and good endosomal escape; moreover, the drug release delivery vehicle for the diagnosis and image-guided chemother- rate can be tuned by changing the interlayer anion. LDHs consist 25,26 2+ 2+ 2+ apy of various cancers . of layers of a divalent metal ion, such as Mg ,Ca ,Ni , and 2+ Carbon nanotubes (CNTs) are synthetic one-dimensional (1D) Zn , with a trivalent metal ion isomorphically substituted to give nanomaterials made from carbon, and they structurally contain the layers a net positive charge . This charge is balanced by rolled sheets of graphene rings built from sp hybridized carbon interlayer hydrated anions, resulting in a multilayer of alternating − − atoms into hollow tubes. CNTs are well known for ideal near- host layers with exchangeable gallery anions, such as Cl ,NO , 2− infrared photothermal ablation therapy because they increase the and CO . Anionic drugs and biofunctional molecules (genetic temperature within tumors as a function of light intensity and CNT materials, peptides, proteins, etc.) can easily be intercalated in the 27,28 dose . Functionalized water-soluble CNTs are being investi- interlayer gallery through direct synthesis, coprecipitation, anion gated for their use in gene and drug delivery because they can exchange, etc., thereby conferring protection against enzymatic 34–36 readily cross biological barriers and can effectively transport degradation while flowing in biological fluids . In addition, 29,30 molecules into the cytoplasm without producing a toxic effect . their internal and/or external surfaces can easily be functionalized Chemotherapeutic drug molecules have been conjugated to and modified to incorporate a targeting function, and their high functional groups on the CNT surface or through polymer coatings specific surface area and better chemical stability make them of CNTs, which are usually formed via cleavable bonds. CNTs for attractive for diverse applications. LDHs can intercalate various antitumor immunotherapy can act as antigen-presenting carriers important anionic biofunctional molecules, such as DNA, siRNA, to improve weakly immunogenic tumor-based peptides/antigens nucleotides and anticancer drugs, showing sustained delivery with 31,32 to trigger a humeral immune response within the tumor . high therapeutic efficiency and bioactivity. A unique strategy for Fig. 1 In vitro and in vivo controlled release of drug using layered double hydroxides and its effects. a In vitro drug release profiles for drug intercalated nitrate, carbonate and phosphate LDHs (LN-R, LC-R and LP-R, respectively); inset figure describes the release pattern of the above mentioned systems in a time frame of 0–8h; b In vitro cytotoxicity of free drug and drug intercalated LDHs against HeLa cells at different time intervals; c In vivo antitumor effect and systematic toxicity of pure RH and drug intercalated LDHs in comparison to control; and d Histological analysis of liver, kidney and spleen of tumor bearing mice treated with control (saline), pure RH, LN-R and LP-R Signal Transduction and Targeted Therapy (2018) 3:7 Drug Delivery Vehicles for Cancer Treatment Senapati et al. Fig. 2 Effect of surface modification on magnetic nanoparticle on hypothermia to reduce tumor size. a Schematic presentation showing the composition of the 4-tetracarboxyphenyl porphyrin (TCPP)-labeled, dopamine-anchored tetraethylene glycol ligands coated bimagnetic Fe/ Fe3O4 nanoparticles; b Graph illustrating the temperature profiles at the MNP injection site in the body core during alternating magnetic field (AMF) exposure, which is measured with a fiber optic temperature probe; c In vivo antitumor response after intratumoral injection of MNPs followed by AMF treatments. Graph demonstrates the relative changes in average tumor volumes over time of B16–F10 tumor bearing mice that were later injected with either saline or MNP intratumorally with or without AMF treatments the delivery of non-ionic insoluble drugs using LDH as carrier can whereas no damage occurs in mice liver cells treated with LN-R or also be made through micellization . The intercalation of an slow release vehicle (Fig. 1d). Further, positively charged LDH anticancer drug, raloxifene hydrochloride (RH), into a series of nanoparticles can easily penetrate into negatively charged cell magnesium aluminum LDHs with varying interlayer exchangeable membranes through the clathrin-mediated endocytosis pathway. − 2− 3− 38 anions (NO ,CO , and PO ) through an ion exchange Li et al. employed a combined strategy using LDH to 3 3 4 technique has been reported and was found to release the drug simultaneously deliver CD-siRNA and a chemotherapeutic drug in a controlled manner . Figure 1a illustrates the rapid release (5-fluorouracil; 5-FU) to cancer cells, leading to significantly higher rate using phosphate bound LDH-drug (LP-R) while sustained cytotoxicity than single treatments with either CD-siRNA or 5-FU. delivery is obtained using nitrate based LDH (LN-R). Spectroscopic Fullerenes are carbon allotropes with a large spheroidal (XPS, UV–vis) and thermal studies (DSC)studies confirm the strong molecule consisting of a hollow cage of sixty or more atoms. interactions between drug molecules and LDH host layers, which They behave like electron deficient alkenes and react readily with lead to sluggish delivery in LN-R against LP-R. In vitro anticancer electron rich species . The photodynamic effect of two new studies demonstrate better efficacy of cell death using drug decacationic fullerene and red light-harvesting antenna-fullerene intercalated LDHs instead of a pure drug arising from sustained conjugated monoadduct derivatives generated reactive oxygen release of the intercalated drug (Fig. 1b). Among the drug species (ROS) for anticancer therapy. Mesoporous silica nanopar- intercalated LDHs, LP-R/pure drug exhibits better tumor suppres- ticles (MSNs) are extensively used as drug delivery vehicles due to sion efficiency, whereas body weight loss index suggests organ their unique properties, such as their large specific surface area damage. In contrast, LN-R shows slight, slow tumor healing but and pore volume, controllable particle size, ease of functionalizing exhibits minimum body weight loss, indicating a better drug good biocompatibility and ability to provide a physical casing to delivery vehicle (Fig. 1c). Histograms of different organs and protect and house drugs from degeneration or denaturation. analyses of biochemical parameters suggest damaged liver cells of MSNs with tunable pore sizes offer great potential for controlling mice treated with fast release vehicle (pure drug and LP-R), drug loading percentages and release kinetics and can deliver Signal Transduction and Targeted Therapy (2018) 3:7 Drug Delivery Vehicles for Cancer Treatment Senapati et al. antitumor drugs in a targeted fashion, releasing them on demand targeted therapy and applications in cancer treatment have been to increase their cellular uptake without any premature release reported . Monocrystalline iron oxide nanoparticles (MION) and prior to reaching the target site . Another advantage of MSNs is crosslinked iron oxide nanoparticles (CLIO) are two typical their ability to deliver membrane impermeable hydrophobic examples of dextran-coated SPIONs and have been widely used 57,58 drugs, thereby serving as a universal transmembrane carrier for in vivo and in vitro MRI . Anti-biofouling polymer coated intracellular drug delivery and imaging applications. They also thermally crosslinked superparamagnetic iron oxide nanoparticles have emerged as promising candidates for both passive and (TCL-SPIONs) act as a novel MR contrast agent for in vivo cancer active targeted delivery systems and can accumulate in tumor imaging and Cy 5.5-conjugated TCL-SPIONs act as a dual (MR/ tissues via the enhanced permeation and retention (EPR) effect. optical) cancer-imaging probe . SPIONs have the potential to Furthermore, specific drug delivery can be achieved via active cure cancer by generating local heat when exposed to an targeting by the functionalizing of MSNs with targeting ligands, alternating magnetic field. Cancer cells are susceptible to such as folate (FA) or EGF . Antibodies, peptides, and magnetic hyperthermia when the temperature increases to ∼43 °C for 61,62 nanoparticles can also be decorated onto MSNs, thereby acting as 30–60 min, which triggers apoptosis . Porphyrin-tethered, a homing device. In the targeting process, particle size and surface dopamine-oligoethylene glycol ligand coated bimagnetic Fe/ modification of MSNs critically influence particle cellular uptake, Fe O nanoparticles act as a significant antitumor agent on 3 4 pharmacokinetics, and biodistribution profiles. murine B16-F10 mice with three short 10 min alternating Calcium phosphate nanoparticles (CPN) have long been magnetic field (AMF) exposures (Fig. 2) . However, hyperthermia regarded as potential drug and gene delivery vehicles due to alone has not been found to be sufficient for cancer treatment, their excellent biocompatibility, biodegradability, and colloidal and it is often used as an adjuvant to other forms of therapy, such stability, and they can encapsulate negatively charged therapeutic as surgery, radiotherapy, and chemotherapy . Thus, recent agents by chelating calcium ions while forming calcium phos- research has focused on combining chemotherapy and hyperther- 42,43 phate nanocrystals . CPN is the major component of bone and mia using multifunctional SPIONs. Phospholipid-PEG coated 2+ 3− tooth enamel, and both Ca and PO are found in the SPIONs have the potential to concurrently deliver doxorubicin 44,45 65 bloodstream at a relatively high concentration (1–5 mM) . and generate heat for enhanced multimodal cancer treatment . Lipid calcium phosphate (LCP) nanoparticles have been found to achieve both systemic delivery of drugs/genes to the lymphatic Organic nanocarriers. Polymeric nanoparticles are solid, biocom- system and imaging of lymph node metastasis . PEGylated patible, colloidal and often biodegradable systems with nanoscale calcium phosphate hybrid micelles enhance the in vivo accumula- dimensions. Polymeric nanoparticles are one of the simplest forms tion of SiRNA in tumor tissues and promote their gene-silencing of soft materials for nanomedicine applications due to their facile activity . Calcium phosphate-based organic–inorganic nanocar- synthesis and easy structural modification to allow desired riers are known for switching on photodynamic therapy in properties to be built into the nanoparticle, such as surface 48 2+ response to acidic environments .Mn within calcium phos- modifications to improve drug loading efficacy, biodistribution, 65,66 phate nanoparticles of poly(ethylene glycol) shells has been found pharmacokinetic control and therapeutic efficacy . Polymeric to act as an efficient magnetic resonance imaging (MRI) contrast nanoparticles can be made from synthetic polymers, e.g., poly agent that rapidly amplifies magnetic resonance signals in (lactic acid) (PLA), poly(ε-caprolactone) (PCL), poly(lactic-co-glyco- response to pH . lic acid), N-(2-hydroxypropyl)-methacrylamide copolymer (HPMA) Superparamagnetic iron oxide nanoparticles (SPIONs) are and poly(styrene-maleic anhydride) copolymer, or from natural receiving increased attention for chemotherapy, hypothermia, polymers, such as gelatin, dextran, guar gum, chitosan, and magnetic resonance imaging (MRI), tissue engineering, cell and collagen. Drugs can easily be encapsulated either through tissue targeting and transfection due to their intrinsic properties, dispersion in the polymer matrix or conjugation/attachment to such as inherent magnetism, visualization by magnetic resonance polymer molecules for their controlled delivery through surface or (MR) imaging, biocompatibility, guidance to target sites by means bulk erosion, diffusion through the polymer matrix, swelling of an external magnetic field, heating to provide hyperthermia for followed by diffusion, or as a response to local stimuli. Synthetic cancer therapy and degradation into nontoxic iron ions in vivo. polymers have the advantage of sustained release over a period of SPIONs are composed of an inner magnetic particle core (usually days to several weeks compared to the relatively shorter duration magnetite, Fe O , or maghemite, γ-Fe O ) and a hydrophilic of drug release of natural polymers; their other benefits include 3 4 2 3 coating of polymers, such as polysaccharide, poly(ethylene glycol) the use of organic solvents and the requirement of typical (PEG), and poly(vinyl alcohol). Direct use of SPIONs without any conditions during encapsulation. Polymeric nanoparticles have polymer coating as an in vivo MRI contrast agent results in therefore been widely investigated as drug delivery systems over biofouling of the particles in blood plasma and particle the last few decades, including the clinical study of FDA-approved agglomerations that are quickly sequestered by cells of the biodegradable polymeric nanoparticles, such as PLA and PLGA. A 50,51 reticular endothelial system (RES), such as macrophages . The drug (doxorubicin) has been conjugated with dextran and coating helps to shield the magnetic particle from the surrounding subsequently encapsulated in a hydrogel using a reverse environment and can also be functionalized by targeting ligands. microemulsion technique reduce its cytotoxic effects and improve These magnetic drug-bearing nanocarriers rely on external its therapeutic efficacy in the treatment of solid tumors . magnetic field guidance to reach their target tissue. Magnetic Tamoxifen embedded PLGA nanoparticles, which were prepared albumin microspheres (MM-ADR) in animal tumor models exhibit using an emulsified nanoprecipitation technique, exhibit DNA better responses than adriamycin alone both in terms of tumor cleavage potential and greater in vitro anticancer activity than the 52 68 size reduction and animal survival . The enhanced efficacy of pure drug . Multifunctional Taxol-loaded PLGA nanoparticles magnetic albumin microspheres in the targeted delivery of an show chemotherapeutic and near-infrared photothermal destruc- anticancer agent compared to the pure drug in rat model is tion of cancer cells in vitro and in vivo . However, by carefully predominantly due to magnetic effects and is not due to the manipulating the drug-to-polymer ratio, molecular weight, and particle’s size or nonmagnetic holding . SPION based MRI is a nature of polymer, the extent and level of drug release from very powerful non-invasive tool in biomedical imaging, clinical nanoparticles can be fine-tuned for effective cancer treatment. diagnosis, and therapy. SPIONs potentially provide higher contrast Liposomes are small, spherical, self-closed structures with at enhancement in MRI and are much more bio-friendly than least one concentric lipid bilayer and an encapsulated aqueous 54,55 conventional paramagnetic Gd-based contrast agents . Various phase in the center. They have been widely used as drug delivery methods of SPION preparation along with functionalization for vehicles since their discovery in 1965 due to their biocompatible Signal Transduction and Targeted Therapy (2018) 3:7 Drug Delivery Vehicles for Cancer Treatment Senapati et al. Fig. 3 Co-asembly of drug and photo photosensitizer for better imaging of tumor size during treatment. a Schematic representation of carrier-free nanoparticles (NPs) via co-assembly between DOX and Ce6; b In vivo fluorescence images of free Ce6 solution and Dox/Ce6 nanoparticles (NPs). The areas in the black circles represent tumor tissue; c Representative ex vivo fluorescence imaging of tumor and organs excised from Balb/c nude mice xenografted MCF-7 tumor at 24 h post-injection and biodegradable nature and their unique ability to encapsulate endothelial growth factors (VEGF), which are often over expressed hydrophilic agents (hydrophilic drugs, DNA, RNA, etc.) in their in many cancers associated with angiogenesis, are induced at a inner aqueous core and hydrophobic drugs within the lamellae, transcriptional level and suppress VEGF and other genes using which makes them versatile therapeutic carriers. Furthermore, RNA interference (RNAi), which is considered to be a novel amphiphilic drugs can also be loaded into the liposome inner therapeutic strategy in the silencing of disease-causing genes. aqueous core using remote loading methods, such as the Chitosan-coated liposomal formulations, such as the siRNA ammonium sulfate method for doxorubicin or the pH gradient delivery system, is effective at achieving gene silencing effi- 71 78 method for vincristine . However, one of the major drawbacks of ciency . Paclitaxel containing A7RC peptide modified liposomes these conventional liposomes was their rapid clearance from the acts as an antimitotic chemotherapeutic drug, which can be a bloodstream. The development of stealth liposomes is underway promising strategy for promoting antitumor and antiangiogenic by utilizing the surface coating of a hydrophilic polymer, usually a therapies . lipid derivative of polyethylene glycol (PEG), to extend the circulation half-life of liposomes from less than a few minutes Protein-based nanocarriers: Albumin is a protein that can be (conventional liposomes) to several hours (stealth liposomes) . obtained from a variety of sources, including egg white Liposomes have the potential to target specific cells through both (ovalbumin), bovine serum (bovine serum albumin, BSA), and active and passive targeting strategies. PEGylated liposomes have human serum (human serum albumin, HSA), and is available in been found to be more effective at passively targeting cancer cells soybeans, milk, and grains. Albumin-based nanocarriers have both in vitro and in vivo than conventional liposomes, and several advantages, such as easy preparation, a high binding moreover, PEGylated liposomes exhibit a high degree of nuclear capacity for various drugs, nontoxic, non-immunogenic, biocom- transfection. Liposomal antisense oligonucleotides (ASO) have patible, and biodegradable properties, and along half-life in been found to be effective for the inhibition of pump and circulating plasma. The presence of functional groups (amino and nonpump resistance of multidrug resistant tumors . Ligand- carboxylic groups) on albumin nanoparticles surfaces makes it targeted liposomes have been found to promote the internaliza- easy to bind targeting ligands and other surface modifications . tion of liposome-drug conjugates into specific target cells both Doxorubicin loaded human serum albumin (HSA) nanoparticles in vitro and in vivo, and the vectors can be designed to release have been found to have better in vitro antitumor efficacy than their contents in the enzyme rich, low pH environment of the pure drug against neuroblastoma cell lines (UKF-NB3 and IMR 74,75 81 endosomes and lysosomes using pH-triggered approaches . 32) . Paclitaxel-loaded bovine serum albumin (BSA) nanoparticles, Targeted zwitterionic oligopeptide liposomes exhibit enhanced which are prepared using a desolvation technique, followed by tumor cell uptake, improved cytoplasmic distribution and folic acid decoration, have been found to target human prostate 76 82 enhanced mitochondrial targeting . A couple of clinically cancer cell line (PC3) effectively . Albumin is a natural carrier of approved liposomal products are on the market and more are hydrophobic molecules (hormones, vitamins and other plasma under clinical development (Table 1). Interestingly, all of these constituents) through favorable, noncovalent reversible binding approved liposomal nanocarriers act through passive targeting and helps with their transportation in body fluids and release at strategies, whereas few targeted formulations have progressed the cell surface. Moreover, albumin can bind to the glycoprotein into the clinic. Ceramide liposomes show an inhibitory effect on (gp60) receptor and mediate the transcytosis of albumin-bound 83,84 peritoneal metastasis in a murine xenograft model of human molecules . Abraxane (nab-paclitaxel; paclitaxel-albumin nano- ovarian cancer and suppress the cell mortality of prometastatic particle), which has an approximate diameter of 130 nm, is the first factor, which is promoted by epithelial growth factor . Vascular FDA-approved commercial product based on the nab platform Signal Transduction and Targeted Therapy (2018) 3:7 Drug Delivery Vehicles for Cancer Treatment Senapati et al. that has shown significant benefits in the treatment of metastatic restoration of a fluorescence signal. The cellular transport of breast cancer. Several other nab-technology based chemother- functional D-peptide derivatives relies on the use of taurine apeutics, such as nab-docetaxel, have already entered into clinical triggered intracellular self-assembly of the D-peptide derivative. trials. Intracellular nanofibers formed by enzyme-instructed self-assem- bly can disrupt actin filaments and enhance the activity of Micelles as a drug carrier: Micelles are spherical or globular cisplatin against drug-resistant ovarian cancer cells by controlling colloidal nanoscale systems formed by self-assembly of amphi- the fate of live cells . Tumor-targeted delivery of siRNA by self- philic block copolymers in an aqueous solution, resulting in a assembled nanoparticles is obtained by mixing carrier DNA, siRNA, hydrophobic core and a hydrophilic shell. They belong to a group protamine and lipids, followed by post-modification with poly of amphiphilic colloids that can be formed spontaneously under (ethylene glycol) and a ligand, anisamide. Forty percent tumor certain concentrations (critical micelle concentration; CMC) and growth inhibition was achieved by treatment with targeted temperatures. The hydrophobic core serves as a reservoir for nanoparticles, and complete inhibition lasted for 1 week when hydrophobic drugs, whereas the hydrophilic shell stabilizes the combined with cisplatin . hydrophobic core and renders both polymer and hydrophobic drugs water soluble, making the particle an appropriate candidate Supramolecules as a delivery vehicle: Supramolecules are an for i.v. administration. The drugs are incorporated into a polymeric assembly of two or more molecular entities stabilized by weak and micelle through physical, chemical, or electrostatic interactions . reversible noncovalent interactions, such as hydrogen bonding, The first polymeric micelle formulation of paclitaxel, Genexol-PM metal coordination, hydrophobic attractions, van der Waals forces, (PEG-poly(D,L-lactide)-paclitaxel), is Cremophor-free polymeric π−π and electrostatic interactions. Therefore, they are expected to micelle-formulated paclitaxel, which can be administered without function as a carrier in drug delivery designs. Supramolecular reactions and shows a favorable toxicity profile with advanced systems can provide vehicles for the encapsulation and targeted 85 96 refractory malignancies . Multifunctional star-shaped polymeric delivery of therapeutic agents or bioactive materials . The toxicity micelles, based on four-arm disulfide linked poly(ε-caprolactone)- of traditional anticancer drugs, such as doxorubicin, can be poly(ethylene glycol) amphiphilic copolymers coupled with folate repressed using amphiphilic dendrimers that generate supramo- ligands,exhibit high stability and sustained release, whereas lecular micelles for cancer therapy . DOX-loaded supramolecular prompt release can occur in an acidic environment . Doxorubicin polymersomes exhibit prolonged circulation in the bloodstream, is encapsulated into cationic 1,2-dioleoyl-3-trimethylammonium and in vivo studies show that they have better antitumor efficacy propane/methoxy poly(ethyleneglycol) (DPP) nanoparticles to towards cancerous HeLa cells with relatively lower cytotoxicity . form micelles for intravesical drug delivery and has shown an Cyclodextrin containing cationic polymer-based supramolecular anticancer effect against bladder cancer . Cholesterol-modified hydrogels show reduced cytotoxicity compared to their non-CD- mPEG–PLA micelles (mPEG–PLA-Ch) exhibit high encapsulation containing polymer counterparts . The temperature responsive efficiency and reduce tumor size considerably compared to the behavior of poly(N-isopropylacrylamide) supramolecular micelles pure drug (curcumin) . Phenylboronic acid (PBA) can selectively and rapid drug release rate are due to induced physical recognize sialic acid (SA), showing a high affinity for targeting crosslinking; however, these supramolecular micelles demonstrate sialylated epitopes that are over expressed on cancer cells, and excellent biocompatibility against most cell lines . oxaliplatin incorporated micelles exhibit enhanced tumor- Dankerset al. introduced a new concept of transient supramo- targeting ability through specific interactions with SA (as lecular networks in which macroscopic rheological and materials confirmed using fluorescence spectroscopy), leading to an properties are tuned by controlled microscopic supramolecular attractive strategy for increasing the efficiency of chemothera- interactions; these interactions are responsible for network 89 90 pies . Gilbreth et al. explored the use of lipid- and polyion formation and lead to promising protein delivery carriers in complex-based micelles for the rapid generation of multivalent regenerative medical applications, such as the proof-of-concept agonists targeting tumor necrosis factor receptors, and the showed in kidney regeneration. Real-time observation of drug micelles showed promising therapeutic efficacy. distributions by supramolecular nanocarriers for the treatment of pancreatic tumors has been investigated to obtain feedback on Self-assembly as a drug carrier: Molecular self-assembly is a free therapeutic efficacy at an early stage. There is no drug energy driven process that spontaneously organizes molecules accumulation in healthy pancreas, which is supported by the into ordered structures in multiple geometries. Therefore, self- strong diagnostic and anticancer effect of supramolecular assembly is a very attractive approach to constructing nanoscale micelles . Tumor-targeted drug delivery systems based on based bioactive materials due to its straightforward use in supramolecular interactions between iron oxide–carbon nano- biomedical applications, including tissue engineering, regenera- tubes and polyamidoamine–polyethylene glycol–polyamidoamine tive medicine and drug delivery. The great advantage of self- (PAMAM–PEG–PAMAM) linear-dendritic copolymers are used as assemblies in its structural features, which can be tuned through promising systems for future cancer therapy with low drug molecular chemistry and environmental conditions (pH, ionic doses . Porphysome nanovesicles are formed through the self- strength, solvents, and temperature) . Self-assembly of the assembly of porphyrin-lipid bilayers that generate unique photosensitizer (chlorine e6, Ce6) and a chemotherapeutic agent fluorescence, photothermal and photoacoustic properties. The (doxorubicin) linked with electrostatic, π−π stacking and hydro- drug loading capacities of porphysomes to destroy tumors by phobic interactions are designed to inhibit tumor recurrence releasing heat are due to their ability to absorb light in the near- (Fig. 3a). Intravenously administeredfree Ce6 and NPs were infrared region, which generates a photoacoustic signal that can distributed throughout the body, whereas the administered self- then be converted into an image. Porphysomes are stable for assembly drugs accumulated in the tumor site exclusively (Fig. 3b). months when stored in aqueous solutions, but they are prone to Ex vivo imaging of excised tumors further confirmed higher drug enzymatic degradation when incubated with detergent and accumulation in tumors with NPs than with free Ce6 solution lipase. The mice in the porphysome and laser-treated group (Fig. 3c) . developed eschars on the tumors (which healed) and their tumors 104 105 The switchable aptamer-diacyllipid conjugates, formed by the were destroyed . Muhannaet al. demonstrated the effective- self-assembly of an aptamer switch probe-diacyllipid chimera, ness of porphysome nanoparticles to enhance fluorescence and showed good results in molecular imaging for bioanalysis, disease photoacoustic imaging of oral cavity carcinomas in rabbit and diagnosis and drug delivery . Upon target binding, the con- hamster models along with tumor-localized photothermal therapy formation of switchable aptamer was altered, resulting in the (PTT). PTT can be precisely guided by both fluorescence imaging Signal Transduction and Targeted Therapy (2018) 3:7 Drug Delivery Vehicles for Cancer Treatment Senapati et al. (control of laser placement and tumor delineation) and photo- which allows them to swell in aqueous media . Hydrogels are acoustic imaging (tumor margin delineation and assessment of widely used for numerous applications in the pharmaceutical and effective PTT doses) for effective therapeutic efficacy. A tailor- medical fields, e.g., as biosensors, materials for contact lenses, made porphyrin based micelle, self-assembled from a hybrid artificial skin, and lining for artificial hearts. Moreover, they can 108,109 amphiphilic polymer comprising polyethylene glycol, poly (D,L- also be used for 3D cell culture and as drug delivery vehicles . lactide-co-glycolide) and porphyrin, loaded with two chemother- Hydrogels are efficient candidates for controlled release, bioadhe- apeutic drugs with synergistic cytotoxicity showed a tendency to sive and/or targeted drug delivery as they can encapsulate accumulate in tumor cells. Drug-loaded micelles improved biomacromolecules, including proteins and DNA, and hydrophilic therapeutic efficacy against triple-negative breast cancer through or hydrophobic drugs . Hydrogel-based drug delivery systems the synergistic effects of photothermal therapy, DOX, and TAX can be used in different ways for oral, rectal, ocular, epidermal, 106 107 with biocompatible polymers and porphyrin . and subcutaneous applications . The key success of hydrogel development is in situ gelation. Hydrogels can be prepared by Hydrogel as a delivery vehicle introducing non-reversible covalent bonds via self-assembly either Hydrogels are three-dimensional (3D) polymeric and hydrophilic through reversible interactions or non-reversible chemical reac- networks that can absorb large amounts of water or biological tions or by UV/photo polymerization. The gelation process is time fluids. Hydrogels are thermodynamically compatible with water, and concentration dependent and can be triggered by an external Fig. 4 Control delivery of drug using hydrogel as vehicle. a Illustration of the preparation and drug release of Salecan/PMAA semi-IPN hydrogels; b In vitro Dox release behaviors from the semi-IPN sample at two different pH values of 5.0 and 7.4; c Fluorescent microscopy images of A549 and HepG2 cells after 4 h of incubation with 6 μg/mL free Dox solutions and the extract liquid of Dox-loaded hydrogel; d Intravital real-time fluorescence images of ICR mice injected with FITC-labeled PMAA nanohydrogels Signal Transduction and Targeted Therapy (2018) 3:7 Drug Delivery Vehicles for Cancer Treatment Senapati et al. stimulus, such as pH, temperature, or light . Hydrogels have drug release; (iv) ease of synthesis; (v) response to external stimuli; 124,125 been found to be biocompatible with negligible cytotoxicity and and (vi) low inherent toxicity . Nanogels act like a soft can be utilized as a delivery platform when accessed with the material when exposed to aqueous media with high water normal cell line COS7 and cancer cell lines HepG2 and A549. A content. Protease/redox/pH stimuli-responsive PEGylated poly variety of innovative semi-interpenetrating polymer network (methacrylic acid) PMAA nanohydrogels have been synthesized (semi-IPN) hydrogels consisting of salecan and poly(methacrylic using cystamine as crosslinker for targeted anticancer drug acid) (PMAA) are formed via free-radical polymerization for delivery . The cumulative release profile indicates greater release controlled drug delivery (Fig. 4a) . Drug release is facilitated in acidic media (pH ~ 5.0) and reducing environments (GSH). under acidic conditions as protonated PMAA disrupts the Intravital real-time fluorescence image analysis indicates the quick electrostatic interaction between DOX and the hydrogel (pH < accumulation and maintenance of FITC-labeled PMAA nanohy- 5.5), favoring drug release compared the conditions at to pH ~ 7.0 drogels in the kidney, liver, and other organs, such as the heart, (Fig. 4b). Due to this factor, pH ~ 5 is considered representative of lung, and spleen; after 30 min of administration, extended in vivo simulated cancer environments. Successive exposure to a different blood circulation lifetimes have been shown using PEGylated FITC- release media at pH 7.4 and 5.0 causes pH-dependent ‘off-on’ labeled PMAA nanohydrogels (Fig. 4d). Yang et al. prepared switching of drug release. Cellular uptake of DOX released from poly(N-isopropylacrylamide)-ss-acrylic acid (P(NIPAM-ss-AA)) nano- drug-loaded hydrogels has effectively been shown in A549 and gels based on NIPAM and AA crosslinked by N,Nʹ-bis(acryloyl) HepG2 cells, showing great promise for hydrogels to be utilized as cystamine (BAC) through precipitation polymerization, which a vehicle for anticancer drug delivery (Fig. 4c). Poly(vinyl exhibited pH/redox dual-responsive DOX release in vitro and in pyrrolidone) stabilized fluorescent red copper nanoclusters can tumor cells. Animal studies have demonstrated the efficient be converted into hydrogel nanocarriers through crosslinking with penetration of DOX-loaded nanogels with fewer side effects, poly(vinyl alcohol) to deliver the anticancer drug cisplatin (CP) to indicating a prospective platform for intracellular controlled drug cervical cancer cells (HeLa), thereby inducing apoptotic cell release in cancer therapy. Bovine serum albumin (BSA) and death . The high encapsulating efficiency is attributed to chitosan (CS) nanogels prepared via a green self-assembly 128,129 molecule loading on the surface and inside the hydrogel particle, technique exhibit slow release with lower cytotoxicity . followed by strong interactions using various functionalities, such Biocompatible and pH-responsive self-assembled nanogels of as −COOH. The slow release of CP at physiological pH is due to chitosan-graft-poly(N-isopropylacrylamide) have been used as a stronger bonding between the drug molecule and the hydrogel, model tumor-targeting delivery system and had greater activity in which can be disrupted at acidic pH, favoring fast release. The acidic media . Alginate-PAMAM dendrimer-based hybrid nano- significant decrease in cell viability in the presence of drug-loaded gels have been developed for drug delivery to cancer cells, and carriers as opposed to free drug molecules reveals the combina- they showed pH-dependent release behavior in a sustained tion of Cu NC−hydrogel composites and CP as a potential material way . Nanocarriers have been found to release more drug in for the design of new chemotherapeutic agents. Doxorubicin acidic environments (mimicking tumor microenvironments) than loaded poly(methacrylic acid) (PMAA) hydrogel cubes and spheres in physiological conditions. are capable of both intracellular degradation and pH- Nanotechnology is a rapidly growing research area in the field responsiveness by introducing cystamine crosslinks within net- of catalysts, biosensors, bioimaging, energy devices, and targeted 114 132–134 works . The membrane adhesion process in the initial step of drug delivery . The large surface-to-volume ratio of nano- cell internalization is greatly affected by the shape of the particles, particles and their size, ability to carry other compounds, binding and hydrogel spheres exhibit 12% higher cell cytotoxicity than ability and their adsorption properties make them suitable for cubes using HeLa cells for 10 h. Shape and pH-sensitive biomedical applications. Nanoparticles can also improve bioavail- ‘intelligent’ 3D networks with programmable shape-regulating ability, protect drugs from degradation and control release rates, behaviors are promising candidates for the controlled delivery of i.e., provide sustained drug release. These unique characteristics of chemotherapeutics. Doxorubicin encapsulated poly(vinylcaprolac- nanoparticles offer a viable platform for their use as an effective tam) (PVCL)-based biodegradable microgels have been designed drug delivery system . Biodegradable carboxymethyl cellulose/ for stimuli-triggered drug release in acidic or reducing environ- graphene oxide (CMC/GO) nanohybrid hydrogel beads physically ments . DOX-loaded microgels exhibit efficient antitumor crosslink with FeCl .6H O have been used for the controlled 3 2 activity to HeLa cells against nontoxic blank microgels. Supramo- release of an anticancer drug (DOX) . The π–π stacking lecular hybrid hydrogels of α-cyclodextrin and polyethylene interaction between GO and DOX caused higher drug loading modified gold nanocrystals exhibit pH-dependent sustained efficiency. The release profile from hydrogels was highly pH- release of DOX through host–guest interaction . Tetrapeptide- dependent, based on hydrogen bonded interactions and exhib- based thermoreversible, pH-sensitive hydrogels have been ited a faster release at pH ~ 6.8 than in slightly basic media (pH ~ prepared for the slow release of anticancer drugs at physiological 7.4). Furthermore, greater amounts of filler/GO reduced the pH . Hexamethylene diisocyanate (HDI) reacts with Pluronic release rate because of enhanced interactions between the F127 as a chain extender to form a copolymer, and subsequent components. Halloysite nanotubes embedded hybrid hydrogels incorporation of hyaluronic acid (HA) has been used to develop a of poly(hydroxyethyl methacrylate) with sodium hyaluronate were composite hydrogel system with a sol–gel transition at 37 °C, very effective for colon cancer drug delivery . Anticancer drugs, leading to the formation of a nanocomposite injectable hydrogel such as 5-fluorouracil (5-FU), have been encapsulated not only in for drug delivery with controlled release . hydrogel networks but also in halloysite nanotubes using an equilibrium swelling method, followed by pulling and breaking Hybrid materials for controlled drug delivery the vacuum. In vitro release of 5-FU from nanohybrid hydrogels Nanoscale dimension hydrogel particles are often called ‘nano- exhibited pH-dependent controlled release following diffusion- gels’ and are formulated either by physically or chemically controlled non-Fickian transport behavior. 5-FU was also inter- 10,119 crosslinked hydrophilic polymers . Nanogels have been calated within the gallery of natural montmorillonite (Mt) clay, recently exploited in various fields, including diagnostics, chemical which could be compounded using alginate (Alg), followed by a and biochemical sensing, tissue engineering, and cancer imaging, coating with chitosan (CS), to prepare a complex drug release 120–123 138 especially as drug delivery vehicle . Nanogels offer several system with controlled release behavior . The release rate of 5- advantages in therapeutic delivery in comparison to existing FU was found to be retarded when using an Alg–CS/5-FU/Mt nanocarriers: (i) high drug loading capacity; (ii) higher storage nanohybrid system in gastric and intestinal environments. Hybrids stability than liposomes and micelles; (iii) controlled and sustained of nanoclay and chitosan–polylactide blends also released Signal Transduction and Targeted Therapy (2018) 3:7 Drug Delivery Vehicles for Cancer Treatment Senapati et al. Fig. 5 Stimuli-responsive targeted delivery of therapeutic agents. a Schematic illustration of stimuli-responsive DDS; b Schematic diagram of pH and GSH dual-responsive dynamic crosslinked supramolecular network on MSN-SS-(EDA-PGOHMA) and synthetic route with CB assembly; c Design of temperature-sensitive liposomes composed of thermosensitive poly(EOEOVE)-OD4 (i), membrane-forming EYPC (ii), membrane-stabilizing cholesterol (iii), and highly hydrophilic and nontoxic PEG-lipid (iv). Heat-triggered release of DOX from liposomes is illustrated with the structure of poly(EOEOVE)-OD4 paclitaxel in a pronounced manner in basic conditions compared antibacterial smart polymer nanohybrids have the potential to be their release in acidic environments . Biodegradable poly(ε- used for combination cancer therapy. caprolactone)nanohybrid scaffolds with organically modified nanoclay, which were prepared through an electrospinning technique, exhibited sustained delivery of an anticancer drug TARGETED DELIVERY: MECHANISTIC PATHWAY (dexamethasone) vis-à-vis pure polymer by creating a maze or Target-specific deliveries of therapeutic agents are based on ‘tortuous path’ that retarded the diffusion of the drug from the stimuli-responsive factors induced by either endogenous (pH, matrix in the presence of a two-dimensional filler . Biocompa- redox, enzyme) or exogenous stimuli (temperature, acoustic, light) tible polyurethane nanohybrids using an aliphatic diisocyanate as shown in Fig. 5a . pH-sensitive chitosan-based supramole- and aliphatic chain extender with varying chain lengths and 2D cular gel is used for oral drug delivery of insulin. The pH sensitivity nanoclay was designed for sustained drug delivery of an of the nanogel protects insulin while it is in the stomach, and the anticancer drug in which the tortuous path was created through bioadhesivity of chitosan enables prolonged contact with the 141 151 larger crystallites from self-assembly of a hard segmented zone . intestinal mucosae to increase the absorption of insulin . The Graphene-based polyurethane nanohybrids have been prepared drug delivery platform based on mechanized silica nanoparticles by grafting long chain polyurethane onto the surface of (MSNPs), which consists of MSNs vehicles, acid-cleavage inter- functionalized graphene oxide for sustained drug delivery of an mediate linkages and reversible supramolecular nanovalves, was anticancer drug (dexamethasone) . Chemically tagged amine- devised to achieve multimodal controlled release of two drugs, and sulfonate-functionalized graphene within long chain poly- gemcitabine (GEM) and doxorubicin (DOX), by arranging the order urethane molecules has been developed for the sustained release of stimuli in sequence. The release time and dosage of GEM are 143,144 of dexamethasone . A hard segment in pure polyurethane precisely controlled via external voltage, whereas subsequent acid was responsible for delayed drug release, whereas the self- treatment triggers the release of DOX, which is attributed to assembled structure and graphene moieties acted as a barrier for breakage of the intermediate linkages containing ketal groups . the diffusion of loaded drugs in nanohybrids. Several other Dynamic crosslinked supramolecular networks of poly(glycidyl polymer nanoparticle hybrid systems have been reported as methacrylate) derivative chains on mesoporous silica nanoparti- sustained release systems for cancer therapy using different drugs, cles respond well against the dual stimuli of pH and glutathione- 145–149 such as DOX, 5-FU, and MTX . The dual-administration of (GSH-) linkage, which control the release of anticancer drug DOX with MTX had higher cytotoxicity towards T47D breast cancer doxorubicin hydrochloride (DOX) under a simulated tumor cells than free dual drug forms. Dual anticancer drug-loaded intracellular environment (pH = 5.0, CGSH = 2~10 mM). Signal Transduction and Targeted Therapy (2018) 3:7 Drug Delivery Vehicles for Cancer Treatment Senapati et al. Disassembly of the crosslinked polymer network occurs by into tumor bearing mice, and tumor growth is significantly lowering the pH, and cleavage of disulfide bonds efficiently suppressed only when the tumor site is heated to 45 °C for 10 min 153 155 promotes drug release kinetics (Fig. 5b) . Glutathione disulfide after 6–12 h of injection (Fig. 5c) . Biocompatible poly(N-(2- (GSSG) is the oxidized form of glutathione (GSH), which is the hydroxypropyl-methacrylamide) (PHPMA) functionalized cyclodex- major endogenous antioxidant. Glutathione protects biological trin (CD) is the building block that houses two guests, e.g., poly(N, systems from oxidizing factors, such as reactive oxygen species, by N-dimethylacrylamide) (PDMAAm) and poly(N,N-diethylacryla- terminating them; GSH is oxidized to GSSG, and then it is reduced mide) (PDEAAm), prepared via reversible addition−fragmentation back to GSH by glutathione reductase (GR). The unique antimeta- chain transfer (RAFT) polymerization and can form a well-defined static mechanism of glutathione disulfide (GSSG) based liposomes supramolecular ABA triblock copolymer responsive to UV light and completely prevents cell detachment and migration and sig- temperature. CD-based host/guest complexes show thermore- nificantly inhibits cancer cell invasion and has been confirmed as a sponsivity due to the negative enthalpy of complex formation. The potential treatment for cancer metastasis . Temperature- application of these stimuli leads to the disassembly of the triblock sensitive liposomes with temperature-sensitive amphiphilic poly- copolymer, which has been shown to be reversible, and is mer poly(EOEOVE)-OD4 are used for tumor-specific chemother- ultimately responsible for regulated delivery. In case of PDEAAm, apy. DOX encapsulated liposomes are administered intravenously temperature-induced aggregation is observed after heating above Fig. 6 Reslease and cellular uptake of drug using magnetic nanoparticles under magnetic field. a Schematic representation of a four armed PE −PCL immobilized magnetic nanoparticle (MNP); b Schematic representation of DOX-loaded MNP and DOX release under the influence of high field alternating magnetic field (HFAMF); c The release kinetics of MNP 3 (particle size of 3 nm) and MNP 5 (particle size of 5 nm) under the influence of HFAMF at 37 °C; d Cellular uptake study of DOX-loaded MAPM on HeLa cell in the presence of a static magnetic field where the nucleus was stained by DAPI (blue) . The scale bar is 40 μm Signal Transduction and Targeted Therapy (2018) 3:7 Drug Delivery Vehicles for Cancer Treatment Senapati et al. Fig. 7 Electric field guided control release of drug. a General scheme for the application of this system: (i) the nanoparticle-polymer solution is (ii) subcutaneously injected into a mouse, followed by (iii) application of a DC electric field to induce the release of drug cargo inside the nanoparticles; b Released amount of daunorubicin in PBS (pH 7.2) following an applied voltage (0.5 V) duration of 10 s, repeated every 5 min the cloud point of the PDEAAm block . Tripeptide Lys–Phe–Gly DOX into the nanoparticle and its release under the influence (KFG), a biologically important tripeptide, is spontaneously self- of high frequency alternating magnetic fields is schematically assembled into well-defined nanostructures in aqueous media, shown in Fig. 6b. The release profiles at the two different showing an exciting phenomenon of reversible and concentration temperatures are not remarkable, whereas drug release is dependent switching of nanostructures between nanovesicles and considerable (51.5%) under the influence of a magnetic field for nanotubes as evidenced by dynamic light scattering, transmission 1 h (Fig. 6c) as the self-assembled structure ruptures under a electron microscopy and atomic force microscopy studies. The strong magnetic field. This form of magnetically controlled DOX tripeptide vesicles have inner aqueous compartments and are release is quite advanced in magnetically active polymeric stable at pH 7.4, but they rupture rapidly at pH 6. The pH-sensitive micelles and is superior from a patient compliance viewpoint response of the vesicles is exploited for delivery of a chemother- compared to other conventional methods used for drug delivery apeutic anticancer drug (doxorubicin), resulting in enhanced (diffusion, pH, thermal response, etc.). The efficacy of magnetic cytotoxicity for both drug-sensitive and drug-resistant cells. The fields for drug release is indicated by effective intercellular uptake absence of the KFG sequence in the receptor polypeptide chain of after only 0.5 h of incubation in the presence of a magnetic field tyrosine kinase nerve growth factor (Trk NGF) strongly affects the with no incorporation of the drug in absence of the field (Fig. 6d). activation of signaling cascades. Efficient intracellular release of A magnetically driven paclitaxel delivery system has been the drug is confirmed by fluorescence-activated cell sorting designed by incorporating iron oxide and a drug in a palmitoyl analysis, fluorescence microscopy, and confocal microscopy .A chitosan matrix through a nanoprecipitation method for con- combination of an aptamer for target recognition and enzyme trolled drug delivery under magnetic field . Enhanced cell (MCF- phosphatidylcholine 2-acetylhydrolase (PLA2) for rupture of lipid 7) death occurs due to the hyperthermic effects of magnetic bilayer of liposomes containing uranin and gadopentetic acid nanoparticles in the presence of an external magnetic field, (GdDTPA) as signaling agents have been investigated for resulting in a biocompatible and biodegradable carrier for the fluorescence and MRI detection. Thus, aptamer−PLA2 triggers precise delivery of powerful cytotoxic anticancer agents. A the release mechanism via the target-responsive liposome system dramatic change in the amount of drug release is found when for signal transduction and selective recognition of biological the remote magnetic field is switched ‘on’ and ‘off’ using silica molecules . magnetic nanocapsules containing camptothecin (hydrophobic) and doxorubicin (hydrophilic) in drug enriched areas near mouse Magnetic field for cancer treatment breast tumors, and the nanocapsules are effective at reducing Magnetic (micro- or nanoparticles) materials were explored a tumor cell growth . Magnetic carriers for drug delivery using couple of decades ago as potential carriers for specific drug superparamagnetic nickel ferrite nanoparticles functionalized with targeting. External magnetic fieldscan be used as a responsive poly(vinyl alcohol), poly(ethylene oxide) and poly(methacrylic drug delivery system to transport drugs to tumor sites. Recently, acid) (PMAA) and subsequently conjugated with doxorubicin superparamagnetic Fe O magnetic nanoparticles have been anticancer drug have significantly enhanced the release rate 3 4 synthesized through grafting using four armed pentaerythretol under magnetic fields by creating mechanical deformation, which poly(ε-caprolactone) in the form of micelles for magnetically generates compressive and tensile stresses to eject drug 159 162 targeted controlled drug (DOX) delivery (Fig. 6a) . The loading of molecules . Signal Transduction and Targeted Therapy (2018) 3:7 Drug Delivery Vehicles for Cancer Treatment Senapati et al. Fig. 8 Laser guided control drug delivery using MoS for cancer treatment. a Schematic illustration of high-throughput synthesis of MoS -CS 2 2 nanosheets as an NIR photothermal-triggered drug delivery system for efficient cancer therapy. (i, ii) Oleum treatment exfoliation process to produce single-layer MoS nanosheets that are then modified with CS, (iii) DOX loading process, and (iv) NIR photothermal-triggered drug delivery of the MoS nanosheets to the tumor site. b Release profile of DOX in PBS buffer (pH 5.00) in the absence and presence of an 808-nm NIR laser. c Fluorescence images of KB cells treated with free DOX, MoS -CS-DOX, and MoS -CS-DOX under 808-nm NIR irradiation (inset: high 2 2 magnification of the rectangle area) Electric field for cancer therapy graphene oxide composite with a polypyrrole scaffold that had a Attention is being given to stimuli-responsive or ‘smart’ biomater- linear release profile under the influence of voltage stimulation, 163–167 ials in the fields of biotechnology and biomedicine . Stimuli- and dosages were adjusted by altering the magnitude of the 168,169 170,171 responsive materials, which respond to heat ,pH , stimulation, proving on-demand drug delivery. Carbon nanotubes 172,173 174,175 176,177 light , enzymes , and magnetic fields , are widely (CNTs) can act as drug nanoreservoirs by holding drug molecules used in the biomedical arena. Electrical signals are easier to within their inner cavity, releasing them in bioactive form under generate and control than other stimuli. Electric stimuli have electrical stimulations . A polypyrrole coating over CNT drug successfully been utilized to trigger the release of molecules via nanoreservoirs seals the ends of the CNTs, effectively loading the conductive polymeric bulk materials or implantable electronic drug, which allows electrical triggering to release the drug with delivery devices. Drug release systems based on conductive the application of voltage . A dual stimuli (electric field and pH) polymers have successfully been utilized, as they offer the responsive system of chitosan–gold nanocomposites (CGNC) has possibility of drug administration through electrical stimulation. been designed for site specific controlled delivery of the Ge et al. designed an electric field responsive drug delivery anticancer drug 5-FU at the reduced pH of cancer cell system using nanoparticles of the conductive polymer polypyr- environments . role. Polypyrrole nanoparticles serve as a drug reservoir for electric field triggered release when they are embedded in biocompatible Thermal treatment for cancer therapy and biodegradable hydrogels of poly[(D,L-lactic acid)-co-(glycolic Photodynamic therapy is an advanced approach that offers acid)]-b-poly(ethylene oxide)-b-poly-[(D,L-lactic acid)-co-(glycolic control of drug delivery through the use of an external photon acid)] (PLGA-PEG-PLGA) (Fig. 7a). This gel is injectable (solution source to provide active therapeutic release to a targeted area. at low temperature but converts into a gel at body temperature) Chitosan-functionalized MoS (MoS -CS) nanosheets can act as a 2 2 and upon application of an external DC electric field, it releases chemotherapeutic drug nanocarrier for near-infrared (NIR) the drug from the nanogel, allowing the drug to diffuse into the photothermal-triggered drug delivery systems, facilitating the surroundings from the hydrogel. Each electric stimulus releases combination of chemotherapy and photothermal treatment for ~25 ng of drug into the solution (Fig. 7b) with minimal release in cancer therapy . The synthesis procedure of single-layer MoS the absence of an electric field, indicating undesired release from nanosheets and NIR-triggered drug release from MoS nanocar- the hydrogel. This type of delivery system has great advantages riers for cancer therapy are shown in Fig. 8a. Drug release profiles over conventional sustained drug release because the released show a sharp increase upon irradiation with NIR laser followed by dose of this drug can be roughly controlled by either the strength power-dependent release and show nonsignificant release in the or the duration of the electric field. Electrically controlled drug absence of irradiation (Fig. 8b). MoS -CS plays an important role in delivery has been demonstrated by Weaver et al. , who used a regulating the release of DOX molecules and enhances their Signal Transduction and Targeted Therapy (2018) 3:7 Drug Delivery Vehicles for Cancer Treatment Senapati et al. nuclear accumulation under NIR irradiation (Fig. 8c). Effective ahead to monitor the mortality rate due to cancer. Most of treatment of pancreatic cancer in vivo under NIR irradiation has these carriers have been designed and tested in small been carried out, confirming the synergistic efficacy of hyperther- animal models, achieving great therapeutic results; however, the mia and chemotherapy. This kind of nanocarrier offers a new translation of animal results into clinical success has been possibility for better ‘on-demand’ drug delivery systems that can limited. More clinical data are needed to fully understand the enhance antitumor efficacy. Dual-in-dual synergistic therapy advantages and disadvantages of these vehicles. Now, we have based on the use of dual anticancer drug-loaded graphene oxide entered into an era of molecular targeting of cancer that may (GO) stabilized with poloxamer 188 has been developed to further improve the chemotherapeutic index by detecting generate heat and deliver drugs to kill cancer cells under near- malignant cells (active targeting moiety), tracking their location infrared (NIR) laser irradiation . Dual drug (doxorubicin and in the body (real-time in vivo imaging), killing cancer cells irinotecan)-loaded GO (GO-DI) in combination with laser irradia- while producing minimal adverse side effects by sparing tion caused higher cytotoxicity than that caused by the normal cells (active targeting and controlled drug release or administration of a free single drug or a combination of drugs hyperthermia ablation) and monitoring the study in real-time. Ion and blank GO in various cancer cells, especially in MDA-MB-231 beam therapy seems to be a promising tool for oncologists to resistant breast cancer cells, suggesting that GO-DI is a powerful treat cancer in near the future instead of high-risk surgery, tool for drug delivery and can achieve improved therapeutic widespread damage from other forms of radiation therapy, such efficacy and overcome drug resistance in combined chemopho- as X-rays, or collateral damage induced by chemotherapeutic tothermal therapy. A photoactivatable o-nitrobenzyl (ONB) deri- drugs. Classic radiation treatment involves mainly X-rays, which vative of 5-fluorouracil (5-FU) attached to the surface of lose energy all along their path through the body and thereby upconverting nanoparticles served as a photocaging nanocarrier damage healthy cells in their path. The beams of protons that absorbed NIR radiation with upconversion in the UV range, or heavier ions, such as carbon and neon, can be accelerated which triggers cleavage of the bonds between ONB-FU at the precisely with calculated energy to accurately target tumor cells, nanoparticle interface to release chemotherapeutic 5-fluorouracil sparing healthy tissue above and below the targeted site. (5-FU) . The main advantage of employing ion beam radiation for cancer The efficiency of triggered release is sufficiently high (77%) treatment is that it has the potential to precisely target any type or for the total ONB−FU conjugate, whereas the rate of drug release form of tumor, which may be very small or large and may be can be tuned with laser power output. The development dangerously shaped or positioned surrounding the spinal cord, in of this type of UCNP provides a valuable platform for targeted the center of the brain or close to the optic nerves. Even though chemotherapy. Thermoresponsive micelles using an amphiphilic proton therapy is commonly used at present, heavier carbon diblock copolymer, poly{γ-2-[2-(2-methoxyethoxy)-ethoxy]ethoxy- ions deposit more energy in tumor tissues. Therefore, ε-caprolactone}-b-poly(γ-octyloxy-ε-caprolactone), display a low carbon or other heavier elements are considerably more critical solution temperature (LCST) of 38 °C and can release the destructive towards the tumor, and hence, they require a fewer therapeutic agent in a controlled fashion . When the anticancer number of doses for treatment. For example, liver cancer requires drug doxorubicin is loaded into the micelle, the micelles exhibit 30 days of treatment using proton therapy, whereas only just four statistically higher cytotoxicity against MCF-7 cells at temperatures days of treatment is sufficient for carbon therapy. Carbon above the LCST. β-cyclodextrin-poly(N-isopropylacrylamide) star therapy provides the highest linear energy transfer (LET) of any polymer is able to form a supramolecular self-assembled inclusion currently available form of clinical radiation. This high energy irradiation to tumor cells results in the destruction of most complex with PTX via host–guest interactions at room tempera- ture, which is below the lower critical solution temperature of the double-stranded DNA; this extensive destruction is very difficult star polymer and significantly improves the solubilization of for other conventional radiation therapies to accomplish, PTX . Phase transitions of poly(N-isopropylacrylamide) segments as they predominantly break single-stranded DNA. Recent at body temperature (above LCST) induce the formation of technological advancements in the fields of accelerator nanoparticles, which greatly enhance cellular uptake of the engineering, beam delivery, treatment planning, and tumor polymer–drug complex, resulting in efficient thermoresponsive visualization have transferred ion beam therapy from physics delivery of PTX. Dual pH/light-responsive crosslinked polymeric laboratories to clinics. micelles (CPM), prepared by the self-assembly of amphiphilic glycol chitosan-o-nitrobenzyl succinate conjugates (GC-NBSCs) and then crosslinked using glutaraldehyde (GA), are used as a drug carrier that can release drugs quickly at low pH under light CONCLUSIONS irradiation . Thus, GC-NBSC CPMs provide a favorable platform This review has summarized a variety of materials that are either to construct dual pH/light-responsive smart drug delivery systems being used or have the potential to be used as drug delivery (DDS) for cancer therapy. Biodegradable plasmon resonant vehicles for the treatment of cancer. Their unique attributes have liposome gold nanoparticles, which are synthesized using 1,2- allowed clinicians to offer them as new treatments (monotherapy) distearoyl-sn-glycero-3-phosphocholine (DSPC)-cholesterol coat- or as adjuncts to existing treatments (combined therapy) to ing with gold nanoparticles, are capable of killing cancer cells improve therapeutic effectiveness. Although some of these through photothermal therapy. materials have not been successful upon their clinical translation, several new and promising materials that are currently under Future challenges in cancer therapy development show great promise, thereby providing hope for Novel drug delivery systems promise a bright future for cancer new treatment options in the near future. treatment in the next decade or so; they might become major arsenal for safer and more efficient treatments by ensuring proper drug localization at the site of action in a controlled manner. The enhanced therapeutic efficacy of targeted nanocarriers has been ACKNOWLEDGEMENTS Research fellowships from UGC (New Delhi, India) (S.S.) and CSIR (New Delhi, India) (A. established in cancer treatment using multiple animal models that K.M.) are gratefully acknowledged. We also acknowledge the Science and target tumors and deliver drugs for targeted radiotherapy, 189,190 Engineering Research Board (Grant No: R&D/SERB/LT/SMST/16/17/06) (SERB) New imaging-guided radiotherapy and precision medicine . Delhi for financial support. We also acknowledge the Council for Scientific and Although major advances have been made by current drug Industrial Research (Grant No. 02(0074)/12/EMR-II) (CSIR-UGC), New Delhi. delivery systems in the treatment of most cancers, much work lies Signal Transduction and Targeted Therapy (2018) 3:7 Drug Delivery Vehicles for Cancer Treatment Senapati et al. ADDITIONAL INFORMATION 29. Lin, Y. et al. Advances toward bioapplications of carbon nanotubes. J. Mater. Conflict of interest: The authors declare that they have no conflict of interest. Chem. 14, 527–541 (2004). 30. Bianco, A., Kostarelos, K. & Prato, M. Applications of carbon nanotubes in drug delivery. Curr. Opin. Chem. Biol. 9, 674–679 (2005). 31. Fadel, T. R. & Fahmy, T. 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Controlled drug delivery vehicles for cancer treatment and their performance

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Medicine & Public Health; Medicine/Public Health, general; Internal Medicine; Cancer Research; Cell Biology; Pathology; Oncology
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Abstract

Signal Transduction and Targeted Therapy www.nature.com/sigtrans REVIEW ARTICLE OPEN Controlled drug delivery vehicles for cancer treatment and their performance 1 1 1 1 Sudipta Senapati , Arun Kumar Mahanta , Sunil Kumar and Pralay Maiti Although conventional chemotherapy has been successful to some extent, the main drawbacks of chemotherapy are its poor bioavailability, high-dose requirements, adverse side effects, low therapeutic indices, development of multiple drug resistance, and non-specific targeting. The main aim in the development of drug delivery vehicles is to successfully address these delivery-related problems and carry drugs to the desired sites of therapeutic action while reducing adverse side effects. In this review, we will discuss the different types of materials used as delivery vehicles for chemotherapeutic agents and their structural characteristics that improve the therapeutic efficacy of their drugs and will describe recent scientific advances in the area of chemotherapy, emphasizing challenges in cancer treatments. Signal Transduction and Targeted Therapy (2018) 3:7 https://doi.org/10.1038/s41392-017-0004-3 INTRODUCTION to address some of these challenges by improving treatment Cancer includes a range of diseases that arise as a result of the efficacy while avoiding toxicity in normal cells due to features unregulated growth of malignant cells, which have the potential such as high selective accumulation in tumors via the enhanced to invade or spread to other body parts. With more than 10 million permeability and retention (EPR) effect and active cellular 12,13 new cases each year, cancer-related deaths are projected to uptake . Active targeting approaches may be achieved by increase in the near future with an estimation by the World Health conjugating nanocarriers containing chemotherapeutics to mole- Organization of ~13.1 million cancer-related deaths by the year cules that bind to over expressed antigens. Among emergent 2030 . However, the mortality rate has decreased in the past 5 nanoscale drug carriers, liposomes, polymeric nanoparticles, and years due to a better understanding of tumor biology and micelles have demonstrated great potential clinical impacts. At improved diagnostic devices and treatments. Current cancer present, several nanoparticle-based chemotherapeutics are clini- treatment options include surgical intervention, chemotherapy, cally approved and many more are in various stages of clinical or and radiation therapy or a combination of these options. preclinical development. Although nanocarriers offer many Conventional chemotherapy works primarily by interfering with advantages as drug carrier systems, their lack of biodegradation, DNA synthesis and mitosis, leading to the death of rapidly poor bioavailability, instability in the circulation, inadequate tissue growing and dividing cancer cells. The agents are nonselective distribution and potential toxicity raise concerns over their safety, and can also damage healthy normal tissues, causing severe especially for long-term administration. Cancer chemoresistance, unintended and undesirable side effects, e.g., loss of appetite and which is accountable for most failure cases in cancer therapy, is a nausea. In fact, the severe adverse effects induced by chemother- phenomenon in which cancer cells that are initially suppressed by apeutic drugs on healthy tissues and organs are a major reason an anticancer drug develop resistance towards the particular drug. behind the high mortality rate of cancer patients. Additionally, as For this reason, novel drug delivery systems with better targeting the bio-accessibility of these drugs to tumor tissues is relatively ability are needed for cancer prevention, the suppression of poor, higher doses are required, leading to elevated toxicity in adverse side effects and pain management associated with cancer normal cells and an increased incidence of multiple drug chemotherapy. resistance. Therefore, it is desirable to develop chemotherapeutics In this review article, we discuss various drug delivery vehicles that can either passively or actively target cancerous cells, thereby used in cancer therapeutics to increase the therapeutic index of reducing adverse side effects while improving therapeutic chemotherapeutic drugs. The performance of basic research to efficacy. In the last few years, a better understanding of tumor clinical studies in the context of present day oncological biology and increased availability of versatile materials, including development is discussed. This review presents current challenges 2–5 6,7 8 9,10 polymers , lipids , inorganic carriers , polymeric hydrogels , associated with chemotherapy, followed by a discussion about the and biomacromolecular scaffolds , have led to the development future directions of chemotherapy. of systems that can deliver chemotherapeutics to tumor sites with improved therapeutic efficacy. The emergence of nanotechnology has had a profound impact on clinical therapeutics in general in MATERIALS AND STRATEGIES USED IN CANCER THERAPY last two decades. Compared to conventional chemotherapeutic Several innovative methods of drug delivery are being used in agents, nanoscale drug carriers have demonstrated the potential cancer treatment. A wide range of nanoscale compounds based School of Materials Science and Technology, Indian Institute of Technology (Banaras Hindu University), Varanasi, India Correspondence: Pralay Maiti (pmaiti.mst@itbhu.ac.in) Received: 31 May 2017 Revised: 16 November 2017 Accepted: 6 December 2017 Drug Delivery Vehicles for Cancer Treatment Senapati et al. Scheme 1 Different types of nanocarriers used as controlled delivery vehicles for cancer treatment on synthetic polymers, proteins, lipids, and organic and inorganic Inorganic nanocarriers. Inorganic nanocarrier platforms have particles have been employed for the development of cancer been intensively investigated for therapeutic and imaging therapeutics. Compared with the direct administration of bare treatments in recent years due to their great advantages, such chemo-drugs, drug encapsulation in a carrier offers a number of as large surface area, better drug loading capacity, better advantages, such as protection from degradation in the blood- bioavailability, lower toxic side effects and controlled drug release, stream, better drug solubility, enhanced drug stability, targeted and their tolerance towards most organic solvents, unlike drug delivery, decreased toxic side effects and improved polymer-based nanoparticles. Quantum dots, carbon nanotubes, pharmacokinetic and pharmacodynamic drug properties. To date, layered double hydroxides, mesoporous silica and magnetic an impressive library of various drug delivery vehicles has been nanoparticles are commonly used in cancer treatment in various developed with varying sizes, architectures, and surface physico- ways. Quantum dots have already been proven to be powerful chemical properties with targeting strategies (Scheme 1). Table 1 imaging probes, especially for long-term, multiplexed and 14–16 summarizes some examples of drug delivery systems that have quantitative imaging and diagnostics . Zero dimensional (0- either been approved or are in clinical or preclinical development D) fluorescent nanoparticles, such as quantum dots (QDs) within stages. the size of 1–10 nm, have emerged as one of the most promising nanoparticles for targeted and traceable drug delivery systems, Nanocarriers for drug delivery real-time monitoring of intracellular processes and in vivo Nanomedicine is a rapidly developing area that is molecular imaging due to their unique physicochemical proper- revolutionizing cancer diagnosis and therapy. Nanoparticles ties, such as uniform size, large surface-to-volume ratio, biocom- have unique biological properties given their small size patibility, highly tunable photoluminescence property, improved (diameter within 1–100 nm) and large surface area to signal brightness, resistance against photobleaching and multi- volume ratio, which allows them to bind, absorb and color fluorescence imaging and detection . However, the main carryanticancer agents, such as drugs, DNA, RNA, and challenge with QDs in biological applications is their hydrophobic proteins, along with imaging agents with high efficiency. nature, high tendency of aggregation and non-specific adsorp- 18,19 Nanocarriers used in chemotherapy can be classified into two tion . QD surfaces are usually coated with polar species and/or major types designed for targeted or non-targeted drug delivery: monolayer or multilayer ligand shells to make them water soluble vehicles that use organic molecules as a major building block and to enhance their bioactivity . This type of coating also helps material and those that use inorganic elements (usually metals) as in the development of multifunctional QDs, where imaging a core. Organic nanocarriers are comprised of liposomes, lipids, contrast agents and small molecular hydrophobic drugs can be dendrimers, carbon nanotubes, emulsions, and synthetic embedded between the inorganic core and the amphiphilic polymers. polymer coating layer while hydrophilic therapeutic agents Signal Transduction and Targeted Therapy (2018) 3:7 1234567890();,: Drug Delivery Vehicles for Cancer Treatment Senapati et al. Signal Transduction and Targeted Therapy (2018) 3:7 Table 1. Various drug delivery carriers used in cancer therapy Material Description of Carrier Commercial Name Material Advantage Specificity Ref Carbon nanotube Anti-P-glycoprotein antibody functionalized Overcomes multidrug resistance Human leukemia cells (K562) 191 CNT-doxorubicin Layered double hydroxide Co-delivery of 5-fluorouracil and siRNAs Overcomes drug resistance and enhances cancer Tested on three different cancer 38 (LDH) treatment cell lines Raloxifene intercalated into the interlayer Enhanced therapeutic efficacy; reduction of adverse side Solid tumor 33 gallery of LDH host effects, pure drug Iron oxide nanoparticles Phospholipid-PEG coated superparamagnetic Nano Therm Both chemotherapy and hyperthermia treatment Solid cancer 192 iron oxide nanoparticles Mesoporous silica Azobenzene-modified mesoporous silica for Drug release rate can be controlled by varying the intensity Solid tumor 193 nanoparticles (MSN) NIR-triggered anticancer drug delivery and/or time Endosomal pH-sensitive MSN for doxorubicin Enhances chemotherapeutic efficacy and overcomes Solid tumor 194 delivery multidrug resistance Polymeric nanoparticles Cyclodextrin-PEG nanoparticles covalently CRLX101 Specifically delivers anticancer agents to tumor tissues and Lung and ovarian cancer 195 conjugated with camptothecin reduces side effects PEG-PLGA nanoparticle formulation of BIND-014 Controlled biodistribution, targeted and preferential tumor Various solid malignancies 196 docetaxel accumulation result in increased efficacy and decreased toxicity Liposomes Liposomal doxorubicin Doxil Improved delivery to site of disease; decrease in systemic Karposi’s sarcoma; Ovarian 197 toxicity of free drug cancer; multiple myeloma Liposomal cytarabine Myocet Increased delivery to tumor site; lower systemic toxicity Intrathecal lymphomatous 198 arising from side effects meningitis Liposomal daunorubicin DaunoXome Enhanced delivery to tumor site; lower systemic toxicity Karposi’s sarcoma 199 arising from side effects Micelle Polymeric methoxy-PEG-poly(D,L-lactide) Genexol-PM Improved delivery to site of disease; decrease in systemic Breast cancer; lung cancer; 200 micelle formulation of paclitaxel toxicity of free drug. ovarian cancer PEG-b-poly(α,β-aspartic acid) nanoparticle NK 105 Enhanced antitumor efficacy and dramatically lower Gastric cancer; breast cancer 201 formulation of paclitaxel neurotoxicity than free paclitaxel Protein nanoparticles Human serum albumin-bound paclitaxel Abraxane Improved solubility; improved delivery to tumor Metastatic breast cancer 202 nanoparticles Folate-conjugated bovine serum albumin- Increased solubility, cellular uptake; targeted specifically to Human prostate cancer cells 82 bound paclitaxel nanoparticles cancer cells (PC3) Dendrimer Carboxylated PAMAM dendrimers covalently Improved loading efficiency, reduced cytotoxicity; Lung cancer cells (NCI-H460) 203 conjugated with cisplatin significant anti-proliferative activity against lung cancer Complexation of doxorubicin with cationic Significant increment in therapeutic efficacy of the drug Solid tumor 204 poly-L-lysine dendrimer upon complexation both in vitro and in vivo Drug Delivery Vehicles for Cancer Treatment Senapati et al. (hydrophilic drug, small interfering RNA (siRNA), etc.) and Among the inorganic nanocarriers, two-dimensional (2D) targeting biomolecules (antibodies, proteins, peptides, and layered double hydroxides (LDHs), also known as hydrotalcite- aptamers) can be immobilized onto the hydrophilic side of the like compounds, have recently attracted a great deal of interest for 21,22 23 amphiphiles . Gao et al. developed polymer encapsulated their potential as delivery carriers mainly because of their and bioconjugated QD probes for cancer targeting and in vivo excellent biocompatibility, anion exchange capability, high drug imaging. d-α-Tocopheryl polyethylene glycol 1000 succinate loading efficacy, full protection for loaded drugs, pH-responsive mono-ester (TPGS) coated multifunctional (theranostic) liposomes drug release, ease of preparation, low cost, easy, and efficient have been developed in the form of docetaxel and QD for cancer- penetration into the cell membrane and considerable drug imaging and targeted therapy . Recently, multifunctional QDs delivery, biodegradation in the cellular cytoplasm (pH between have been synthesized, making them a promising targeted drug 4 and 6), and good endosomal escape; moreover, the drug release delivery vehicle for the diagnosis and image-guided chemother- rate can be tuned by changing the interlayer anion. LDHs consist 25,26 2+ 2+ 2+ apy of various cancers . of layers of a divalent metal ion, such as Mg ,Ca ,Ni , and 2+ Carbon nanotubes (CNTs) are synthetic one-dimensional (1D) Zn , with a trivalent metal ion isomorphically substituted to give nanomaterials made from carbon, and they structurally contain the layers a net positive charge . This charge is balanced by rolled sheets of graphene rings built from sp hybridized carbon interlayer hydrated anions, resulting in a multilayer of alternating − − atoms into hollow tubes. CNTs are well known for ideal near- host layers with exchangeable gallery anions, such as Cl ,NO , 2− infrared photothermal ablation therapy because they increase the and CO . Anionic drugs and biofunctional molecules (genetic temperature within tumors as a function of light intensity and CNT materials, peptides, proteins, etc.) can easily be intercalated in the 27,28 dose . Functionalized water-soluble CNTs are being investi- interlayer gallery through direct synthesis, coprecipitation, anion gated for their use in gene and drug delivery because they can exchange, etc., thereby conferring protection against enzymatic 34–36 readily cross biological barriers and can effectively transport degradation while flowing in biological fluids . In addition, 29,30 molecules into the cytoplasm without producing a toxic effect . their internal and/or external surfaces can easily be functionalized Chemotherapeutic drug molecules have been conjugated to and modified to incorporate a targeting function, and their high functional groups on the CNT surface or through polymer coatings specific surface area and better chemical stability make them of CNTs, which are usually formed via cleavable bonds. CNTs for attractive for diverse applications. LDHs can intercalate various antitumor immunotherapy can act as antigen-presenting carriers important anionic biofunctional molecules, such as DNA, siRNA, to improve weakly immunogenic tumor-based peptides/antigens nucleotides and anticancer drugs, showing sustained delivery with 31,32 to trigger a humeral immune response within the tumor . high therapeutic efficiency and bioactivity. A unique strategy for Fig. 1 In vitro and in vivo controlled release of drug using layered double hydroxides and its effects. a In vitro drug release profiles for drug intercalated nitrate, carbonate and phosphate LDHs (LN-R, LC-R and LP-R, respectively); inset figure describes the release pattern of the above mentioned systems in a time frame of 0–8h; b In vitro cytotoxicity of free drug and drug intercalated LDHs against HeLa cells at different time intervals; c In vivo antitumor effect and systematic toxicity of pure RH and drug intercalated LDHs in comparison to control; and d Histological analysis of liver, kidney and spleen of tumor bearing mice treated with control (saline), pure RH, LN-R and LP-R Signal Transduction and Targeted Therapy (2018) 3:7 Drug Delivery Vehicles for Cancer Treatment Senapati et al. Fig. 2 Effect of surface modification on magnetic nanoparticle on hypothermia to reduce tumor size. a Schematic presentation showing the composition of the 4-tetracarboxyphenyl porphyrin (TCPP)-labeled, dopamine-anchored tetraethylene glycol ligands coated bimagnetic Fe/ Fe3O4 nanoparticles; b Graph illustrating the temperature profiles at the MNP injection site in the body core during alternating magnetic field (AMF) exposure, which is measured with a fiber optic temperature probe; c In vivo antitumor response after intratumoral injection of MNPs followed by AMF treatments. Graph demonstrates the relative changes in average tumor volumes over time of B16–F10 tumor bearing mice that were later injected with either saline or MNP intratumorally with or without AMF treatments the delivery of non-ionic insoluble drugs using LDH as carrier can whereas no damage occurs in mice liver cells treated with LN-R or also be made through micellization . The intercalation of an slow release vehicle (Fig. 1d). Further, positively charged LDH anticancer drug, raloxifene hydrochloride (RH), into a series of nanoparticles can easily penetrate into negatively charged cell magnesium aluminum LDHs with varying interlayer exchangeable membranes through the clathrin-mediated endocytosis pathway. − 2− 3− 38 anions (NO ,CO , and PO ) through an ion exchange Li et al. employed a combined strategy using LDH to 3 3 4 technique has been reported and was found to release the drug simultaneously deliver CD-siRNA and a chemotherapeutic drug in a controlled manner . Figure 1a illustrates the rapid release (5-fluorouracil; 5-FU) to cancer cells, leading to significantly higher rate using phosphate bound LDH-drug (LP-R) while sustained cytotoxicity than single treatments with either CD-siRNA or 5-FU. delivery is obtained using nitrate based LDH (LN-R). Spectroscopic Fullerenes are carbon allotropes with a large spheroidal (XPS, UV–vis) and thermal studies (DSC)studies confirm the strong molecule consisting of a hollow cage of sixty or more atoms. interactions between drug molecules and LDH host layers, which They behave like electron deficient alkenes and react readily with lead to sluggish delivery in LN-R against LP-R. In vitro anticancer electron rich species . The photodynamic effect of two new studies demonstrate better efficacy of cell death using drug decacationic fullerene and red light-harvesting antenna-fullerene intercalated LDHs instead of a pure drug arising from sustained conjugated monoadduct derivatives generated reactive oxygen release of the intercalated drug (Fig. 1b). Among the drug species (ROS) for anticancer therapy. Mesoporous silica nanopar- intercalated LDHs, LP-R/pure drug exhibits better tumor suppres- ticles (MSNs) are extensively used as drug delivery vehicles due to sion efficiency, whereas body weight loss index suggests organ their unique properties, such as their large specific surface area damage. In contrast, LN-R shows slight, slow tumor healing but and pore volume, controllable particle size, ease of functionalizing exhibits minimum body weight loss, indicating a better drug good biocompatibility and ability to provide a physical casing to delivery vehicle (Fig. 1c). Histograms of different organs and protect and house drugs from degeneration or denaturation. analyses of biochemical parameters suggest damaged liver cells of MSNs with tunable pore sizes offer great potential for controlling mice treated with fast release vehicle (pure drug and LP-R), drug loading percentages and release kinetics and can deliver Signal Transduction and Targeted Therapy (2018) 3:7 Drug Delivery Vehicles for Cancer Treatment Senapati et al. antitumor drugs in a targeted fashion, releasing them on demand targeted therapy and applications in cancer treatment have been to increase their cellular uptake without any premature release reported . Monocrystalline iron oxide nanoparticles (MION) and prior to reaching the target site . Another advantage of MSNs is crosslinked iron oxide nanoparticles (CLIO) are two typical their ability to deliver membrane impermeable hydrophobic examples of dextran-coated SPIONs and have been widely used 57,58 drugs, thereby serving as a universal transmembrane carrier for in vivo and in vitro MRI . Anti-biofouling polymer coated intracellular drug delivery and imaging applications. They also thermally crosslinked superparamagnetic iron oxide nanoparticles have emerged as promising candidates for both passive and (TCL-SPIONs) act as a novel MR contrast agent for in vivo cancer active targeted delivery systems and can accumulate in tumor imaging and Cy 5.5-conjugated TCL-SPIONs act as a dual (MR/ tissues via the enhanced permeation and retention (EPR) effect. optical) cancer-imaging probe . SPIONs have the potential to Furthermore, specific drug delivery can be achieved via active cure cancer by generating local heat when exposed to an targeting by the functionalizing of MSNs with targeting ligands, alternating magnetic field. Cancer cells are susceptible to such as folate (FA) or EGF . Antibodies, peptides, and magnetic hyperthermia when the temperature increases to ∼43 °C for 61,62 nanoparticles can also be decorated onto MSNs, thereby acting as 30–60 min, which triggers apoptosis . Porphyrin-tethered, a homing device. In the targeting process, particle size and surface dopamine-oligoethylene glycol ligand coated bimagnetic Fe/ modification of MSNs critically influence particle cellular uptake, Fe O nanoparticles act as a significant antitumor agent on 3 4 pharmacokinetics, and biodistribution profiles. murine B16-F10 mice with three short 10 min alternating Calcium phosphate nanoparticles (CPN) have long been magnetic field (AMF) exposures (Fig. 2) . However, hyperthermia regarded as potential drug and gene delivery vehicles due to alone has not been found to be sufficient for cancer treatment, their excellent biocompatibility, biodegradability, and colloidal and it is often used as an adjuvant to other forms of therapy, such stability, and they can encapsulate negatively charged therapeutic as surgery, radiotherapy, and chemotherapy . Thus, recent agents by chelating calcium ions while forming calcium phos- research has focused on combining chemotherapy and hyperther- 42,43 phate nanocrystals . CPN is the major component of bone and mia using multifunctional SPIONs. Phospholipid-PEG coated 2+ 3− tooth enamel, and both Ca and PO are found in the SPIONs have the potential to concurrently deliver doxorubicin 44,45 65 bloodstream at a relatively high concentration (1–5 mM) . and generate heat for enhanced multimodal cancer treatment . Lipid calcium phosphate (LCP) nanoparticles have been found to achieve both systemic delivery of drugs/genes to the lymphatic Organic nanocarriers. Polymeric nanoparticles are solid, biocom- system and imaging of lymph node metastasis . PEGylated patible, colloidal and often biodegradable systems with nanoscale calcium phosphate hybrid micelles enhance the in vivo accumula- dimensions. Polymeric nanoparticles are one of the simplest forms tion of SiRNA in tumor tissues and promote their gene-silencing of soft materials for nanomedicine applications due to their facile activity . Calcium phosphate-based organic–inorganic nanocar- synthesis and easy structural modification to allow desired riers are known for switching on photodynamic therapy in properties to be built into the nanoparticle, such as surface 48 2+ response to acidic environments .Mn within calcium phos- modifications to improve drug loading efficacy, biodistribution, 65,66 phate nanoparticles of poly(ethylene glycol) shells has been found pharmacokinetic control and therapeutic efficacy . Polymeric to act as an efficient magnetic resonance imaging (MRI) contrast nanoparticles can be made from synthetic polymers, e.g., poly agent that rapidly amplifies magnetic resonance signals in (lactic acid) (PLA), poly(ε-caprolactone) (PCL), poly(lactic-co-glyco- response to pH . lic acid), N-(2-hydroxypropyl)-methacrylamide copolymer (HPMA) Superparamagnetic iron oxide nanoparticles (SPIONs) are and poly(styrene-maleic anhydride) copolymer, or from natural receiving increased attention for chemotherapy, hypothermia, polymers, such as gelatin, dextran, guar gum, chitosan, and magnetic resonance imaging (MRI), tissue engineering, cell and collagen. Drugs can easily be encapsulated either through tissue targeting and transfection due to their intrinsic properties, dispersion in the polymer matrix or conjugation/attachment to such as inherent magnetism, visualization by magnetic resonance polymer molecules for their controlled delivery through surface or (MR) imaging, biocompatibility, guidance to target sites by means bulk erosion, diffusion through the polymer matrix, swelling of an external magnetic field, heating to provide hyperthermia for followed by diffusion, or as a response to local stimuli. Synthetic cancer therapy and degradation into nontoxic iron ions in vivo. polymers have the advantage of sustained release over a period of SPIONs are composed of an inner magnetic particle core (usually days to several weeks compared to the relatively shorter duration magnetite, Fe O , or maghemite, γ-Fe O ) and a hydrophilic of drug release of natural polymers; their other benefits include 3 4 2 3 coating of polymers, such as polysaccharide, poly(ethylene glycol) the use of organic solvents and the requirement of typical (PEG), and poly(vinyl alcohol). Direct use of SPIONs without any conditions during encapsulation. Polymeric nanoparticles have polymer coating as an in vivo MRI contrast agent results in therefore been widely investigated as drug delivery systems over biofouling of the particles in blood plasma and particle the last few decades, including the clinical study of FDA-approved agglomerations that are quickly sequestered by cells of the biodegradable polymeric nanoparticles, such as PLA and PLGA. A 50,51 reticular endothelial system (RES), such as macrophages . The drug (doxorubicin) has been conjugated with dextran and coating helps to shield the magnetic particle from the surrounding subsequently encapsulated in a hydrogel using a reverse environment and can also be functionalized by targeting ligands. microemulsion technique reduce its cytotoxic effects and improve These magnetic drug-bearing nanocarriers rely on external its therapeutic efficacy in the treatment of solid tumors . magnetic field guidance to reach their target tissue. Magnetic Tamoxifen embedded PLGA nanoparticles, which were prepared albumin microspheres (MM-ADR) in animal tumor models exhibit using an emulsified nanoprecipitation technique, exhibit DNA better responses than adriamycin alone both in terms of tumor cleavage potential and greater in vitro anticancer activity than the 52 68 size reduction and animal survival . The enhanced efficacy of pure drug . Multifunctional Taxol-loaded PLGA nanoparticles magnetic albumin microspheres in the targeted delivery of an show chemotherapeutic and near-infrared photothermal destruc- anticancer agent compared to the pure drug in rat model is tion of cancer cells in vitro and in vivo . However, by carefully predominantly due to magnetic effects and is not due to the manipulating the drug-to-polymer ratio, molecular weight, and particle’s size or nonmagnetic holding . SPION based MRI is a nature of polymer, the extent and level of drug release from very powerful non-invasive tool in biomedical imaging, clinical nanoparticles can be fine-tuned for effective cancer treatment. diagnosis, and therapy. SPIONs potentially provide higher contrast Liposomes are small, spherical, self-closed structures with at enhancement in MRI and are much more bio-friendly than least one concentric lipid bilayer and an encapsulated aqueous 54,55 conventional paramagnetic Gd-based contrast agents . Various phase in the center. They have been widely used as drug delivery methods of SPION preparation along with functionalization for vehicles since their discovery in 1965 due to their biocompatible Signal Transduction and Targeted Therapy (2018) 3:7 Drug Delivery Vehicles for Cancer Treatment Senapati et al. Fig. 3 Co-asembly of drug and photo photosensitizer for better imaging of tumor size during treatment. a Schematic representation of carrier-free nanoparticles (NPs) via co-assembly between DOX and Ce6; b In vivo fluorescence images of free Ce6 solution and Dox/Ce6 nanoparticles (NPs). The areas in the black circles represent tumor tissue; c Representative ex vivo fluorescence imaging of tumor and organs excised from Balb/c nude mice xenografted MCF-7 tumor at 24 h post-injection and biodegradable nature and their unique ability to encapsulate endothelial growth factors (VEGF), which are often over expressed hydrophilic agents (hydrophilic drugs, DNA, RNA, etc.) in their in many cancers associated with angiogenesis, are induced at a inner aqueous core and hydrophobic drugs within the lamellae, transcriptional level and suppress VEGF and other genes using which makes them versatile therapeutic carriers. Furthermore, RNA interference (RNAi), which is considered to be a novel amphiphilic drugs can also be loaded into the liposome inner therapeutic strategy in the silencing of disease-causing genes. aqueous core using remote loading methods, such as the Chitosan-coated liposomal formulations, such as the siRNA ammonium sulfate method for doxorubicin or the pH gradient delivery system, is effective at achieving gene silencing effi- 71 78 method for vincristine . However, one of the major drawbacks of ciency . Paclitaxel containing A7RC peptide modified liposomes these conventional liposomes was their rapid clearance from the acts as an antimitotic chemotherapeutic drug, which can be a bloodstream. The development of stealth liposomes is underway promising strategy for promoting antitumor and antiangiogenic by utilizing the surface coating of a hydrophilic polymer, usually a therapies . lipid derivative of polyethylene glycol (PEG), to extend the circulation half-life of liposomes from less than a few minutes Protein-based nanocarriers: Albumin is a protein that can be (conventional liposomes) to several hours (stealth liposomes) . obtained from a variety of sources, including egg white Liposomes have the potential to target specific cells through both (ovalbumin), bovine serum (bovine serum albumin, BSA), and active and passive targeting strategies. PEGylated liposomes have human serum (human serum albumin, HSA), and is available in been found to be more effective at passively targeting cancer cells soybeans, milk, and grains. Albumin-based nanocarriers have both in vitro and in vivo than conventional liposomes, and several advantages, such as easy preparation, a high binding moreover, PEGylated liposomes exhibit a high degree of nuclear capacity for various drugs, nontoxic, non-immunogenic, biocom- transfection. Liposomal antisense oligonucleotides (ASO) have patible, and biodegradable properties, and along half-life in been found to be effective for the inhibition of pump and circulating plasma. The presence of functional groups (amino and nonpump resistance of multidrug resistant tumors . Ligand- carboxylic groups) on albumin nanoparticles surfaces makes it targeted liposomes have been found to promote the internaliza- easy to bind targeting ligands and other surface modifications . tion of liposome-drug conjugates into specific target cells both Doxorubicin loaded human serum albumin (HSA) nanoparticles in vitro and in vivo, and the vectors can be designed to release have been found to have better in vitro antitumor efficacy than their contents in the enzyme rich, low pH environment of the pure drug against neuroblastoma cell lines (UKF-NB3 and IMR 74,75 81 endosomes and lysosomes using pH-triggered approaches . 32) . Paclitaxel-loaded bovine serum albumin (BSA) nanoparticles, Targeted zwitterionic oligopeptide liposomes exhibit enhanced which are prepared using a desolvation technique, followed by tumor cell uptake, improved cytoplasmic distribution and folic acid decoration, have been found to target human prostate 76 82 enhanced mitochondrial targeting . A couple of clinically cancer cell line (PC3) effectively . Albumin is a natural carrier of approved liposomal products are on the market and more are hydrophobic molecules (hormones, vitamins and other plasma under clinical development (Table 1). Interestingly, all of these constituents) through favorable, noncovalent reversible binding approved liposomal nanocarriers act through passive targeting and helps with their transportation in body fluids and release at strategies, whereas few targeted formulations have progressed the cell surface. Moreover, albumin can bind to the glycoprotein into the clinic. Ceramide liposomes show an inhibitory effect on (gp60) receptor and mediate the transcytosis of albumin-bound 83,84 peritoneal metastasis in a murine xenograft model of human molecules . Abraxane (nab-paclitaxel; paclitaxel-albumin nano- ovarian cancer and suppress the cell mortality of prometastatic particle), which has an approximate diameter of 130 nm, is the first factor, which is promoted by epithelial growth factor . Vascular FDA-approved commercial product based on the nab platform Signal Transduction and Targeted Therapy (2018) 3:7 Drug Delivery Vehicles for Cancer Treatment Senapati et al. that has shown significant benefits in the treatment of metastatic restoration of a fluorescence signal. The cellular transport of breast cancer. Several other nab-technology based chemother- functional D-peptide derivatives relies on the use of taurine apeutics, such as nab-docetaxel, have already entered into clinical triggered intracellular self-assembly of the D-peptide derivative. trials. Intracellular nanofibers formed by enzyme-instructed self-assem- bly can disrupt actin filaments and enhance the activity of Micelles as a drug carrier: Micelles are spherical or globular cisplatin against drug-resistant ovarian cancer cells by controlling colloidal nanoscale systems formed by self-assembly of amphi- the fate of live cells . Tumor-targeted delivery of siRNA by self- philic block copolymers in an aqueous solution, resulting in a assembled nanoparticles is obtained by mixing carrier DNA, siRNA, hydrophobic core and a hydrophilic shell. They belong to a group protamine and lipids, followed by post-modification with poly of amphiphilic colloids that can be formed spontaneously under (ethylene glycol) and a ligand, anisamide. Forty percent tumor certain concentrations (critical micelle concentration; CMC) and growth inhibition was achieved by treatment with targeted temperatures. The hydrophobic core serves as a reservoir for nanoparticles, and complete inhibition lasted for 1 week when hydrophobic drugs, whereas the hydrophilic shell stabilizes the combined with cisplatin . hydrophobic core and renders both polymer and hydrophobic drugs water soluble, making the particle an appropriate candidate Supramolecules as a delivery vehicle: Supramolecules are an for i.v. administration. The drugs are incorporated into a polymeric assembly of two or more molecular entities stabilized by weak and micelle through physical, chemical, or electrostatic interactions . reversible noncovalent interactions, such as hydrogen bonding, The first polymeric micelle formulation of paclitaxel, Genexol-PM metal coordination, hydrophobic attractions, van der Waals forces, (PEG-poly(D,L-lactide)-paclitaxel), is Cremophor-free polymeric π−π and electrostatic interactions. Therefore, they are expected to micelle-formulated paclitaxel, which can be administered without function as a carrier in drug delivery designs. Supramolecular reactions and shows a favorable toxicity profile with advanced systems can provide vehicles for the encapsulation and targeted 85 96 refractory malignancies . Multifunctional star-shaped polymeric delivery of therapeutic agents or bioactive materials . The toxicity micelles, based on four-arm disulfide linked poly(ε-caprolactone)- of traditional anticancer drugs, such as doxorubicin, can be poly(ethylene glycol) amphiphilic copolymers coupled with folate repressed using amphiphilic dendrimers that generate supramo- ligands,exhibit high stability and sustained release, whereas lecular micelles for cancer therapy . DOX-loaded supramolecular prompt release can occur in an acidic environment . Doxorubicin polymersomes exhibit prolonged circulation in the bloodstream, is encapsulated into cationic 1,2-dioleoyl-3-trimethylammonium and in vivo studies show that they have better antitumor efficacy propane/methoxy poly(ethyleneglycol) (DPP) nanoparticles to towards cancerous HeLa cells with relatively lower cytotoxicity . form micelles for intravesical drug delivery and has shown an Cyclodextrin containing cationic polymer-based supramolecular anticancer effect against bladder cancer . Cholesterol-modified hydrogels show reduced cytotoxicity compared to their non-CD- mPEG–PLA micelles (mPEG–PLA-Ch) exhibit high encapsulation containing polymer counterparts . The temperature responsive efficiency and reduce tumor size considerably compared to the behavior of poly(N-isopropylacrylamide) supramolecular micelles pure drug (curcumin) . Phenylboronic acid (PBA) can selectively and rapid drug release rate are due to induced physical recognize sialic acid (SA), showing a high affinity for targeting crosslinking; however, these supramolecular micelles demonstrate sialylated epitopes that are over expressed on cancer cells, and excellent biocompatibility against most cell lines . oxaliplatin incorporated micelles exhibit enhanced tumor- Dankerset al. introduced a new concept of transient supramo- targeting ability through specific interactions with SA (as lecular networks in which macroscopic rheological and materials confirmed using fluorescence spectroscopy), leading to an properties are tuned by controlled microscopic supramolecular attractive strategy for increasing the efficiency of chemothera- interactions; these interactions are responsible for network 89 90 pies . Gilbreth et al. explored the use of lipid- and polyion formation and lead to promising protein delivery carriers in complex-based micelles for the rapid generation of multivalent regenerative medical applications, such as the proof-of-concept agonists targeting tumor necrosis factor receptors, and the showed in kidney regeneration. Real-time observation of drug micelles showed promising therapeutic efficacy. distributions by supramolecular nanocarriers for the treatment of pancreatic tumors has been investigated to obtain feedback on Self-assembly as a drug carrier: Molecular self-assembly is a free therapeutic efficacy at an early stage. There is no drug energy driven process that spontaneously organizes molecules accumulation in healthy pancreas, which is supported by the into ordered structures in multiple geometries. Therefore, self- strong diagnostic and anticancer effect of supramolecular assembly is a very attractive approach to constructing nanoscale micelles . Tumor-targeted drug delivery systems based on based bioactive materials due to its straightforward use in supramolecular interactions between iron oxide–carbon nano- biomedical applications, including tissue engineering, regenera- tubes and polyamidoamine–polyethylene glycol–polyamidoamine tive medicine and drug delivery. The great advantage of self- (PAMAM–PEG–PAMAM) linear-dendritic copolymers are used as assemblies in its structural features, which can be tuned through promising systems for future cancer therapy with low drug molecular chemistry and environmental conditions (pH, ionic doses . Porphysome nanovesicles are formed through the self- strength, solvents, and temperature) . Self-assembly of the assembly of porphyrin-lipid bilayers that generate unique photosensitizer (chlorine e6, Ce6) and a chemotherapeutic agent fluorescence, photothermal and photoacoustic properties. The (doxorubicin) linked with electrostatic, π−π stacking and hydro- drug loading capacities of porphysomes to destroy tumors by phobic interactions are designed to inhibit tumor recurrence releasing heat are due to their ability to absorb light in the near- (Fig. 3a). Intravenously administeredfree Ce6 and NPs were infrared region, which generates a photoacoustic signal that can distributed throughout the body, whereas the administered self- then be converted into an image. Porphysomes are stable for assembly drugs accumulated in the tumor site exclusively (Fig. 3b). months when stored in aqueous solutions, but they are prone to Ex vivo imaging of excised tumors further confirmed higher drug enzymatic degradation when incubated with detergent and accumulation in tumors with NPs than with free Ce6 solution lipase. The mice in the porphysome and laser-treated group (Fig. 3c) . developed eschars on the tumors (which healed) and their tumors 104 105 The switchable aptamer-diacyllipid conjugates, formed by the were destroyed . Muhannaet al. demonstrated the effective- self-assembly of an aptamer switch probe-diacyllipid chimera, ness of porphysome nanoparticles to enhance fluorescence and showed good results in molecular imaging for bioanalysis, disease photoacoustic imaging of oral cavity carcinomas in rabbit and diagnosis and drug delivery . Upon target binding, the con- hamster models along with tumor-localized photothermal therapy formation of switchable aptamer was altered, resulting in the (PTT). PTT can be precisely guided by both fluorescence imaging Signal Transduction and Targeted Therapy (2018) 3:7 Drug Delivery Vehicles for Cancer Treatment Senapati et al. (control of laser placement and tumor delineation) and photo- which allows them to swell in aqueous media . Hydrogels are acoustic imaging (tumor margin delineation and assessment of widely used for numerous applications in the pharmaceutical and effective PTT doses) for effective therapeutic efficacy. A tailor- medical fields, e.g., as biosensors, materials for contact lenses, made porphyrin based micelle, self-assembled from a hybrid artificial skin, and lining for artificial hearts. Moreover, they can 108,109 amphiphilic polymer comprising polyethylene glycol, poly (D,L- also be used for 3D cell culture and as drug delivery vehicles . lactide-co-glycolide) and porphyrin, loaded with two chemother- Hydrogels are efficient candidates for controlled release, bioadhe- apeutic drugs with synergistic cytotoxicity showed a tendency to sive and/or targeted drug delivery as they can encapsulate accumulate in tumor cells. Drug-loaded micelles improved biomacromolecules, including proteins and DNA, and hydrophilic therapeutic efficacy against triple-negative breast cancer through or hydrophobic drugs . Hydrogel-based drug delivery systems the synergistic effects of photothermal therapy, DOX, and TAX can be used in different ways for oral, rectal, ocular, epidermal, 106 107 with biocompatible polymers and porphyrin . and subcutaneous applications . The key success of hydrogel development is in situ gelation. Hydrogels can be prepared by Hydrogel as a delivery vehicle introducing non-reversible covalent bonds via self-assembly either Hydrogels are three-dimensional (3D) polymeric and hydrophilic through reversible interactions or non-reversible chemical reac- networks that can absorb large amounts of water or biological tions or by UV/photo polymerization. The gelation process is time fluids. Hydrogels are thermodynamically compatible with water, and concentration dependent and can be triggered by an external Fig. 4 Control delivery of drug using hydrogel as vehicle. a Illustration of the preparation and drug release of Salecan/PMAA semi-IPN hydrogels; b In vitro Dox release behaviors from the semi-IPN sample at two different pH values of 5.0 and 7.4; c Fluorescent microscopy images of A549 and HepG2 cells after 4 h of incubation with 6 μg/mL free Dox solutions and the extract liquid of Dox-loaded hydrogel; d Intravital real-time fluorescence images of ICR mice injected with FITC-labeled PMAA nanohydrogels Signal Transduction and Targeted Therapy (2018) 3:7 Drug Delivery Vehicles for Cancer Treatment Senapati et al. stimulus, such as pH, temperature, or light . Hydrogels have drug release; (iv) ease of synthesis; (v) response to external stimuli; 124,125 been found to be biocompatible with negligible cytotoxicity and and (vi) low inherent toxicity . Nanogels act like a soft can be utilized as a delivery platform when accessed with the material when exposed to aqueous media with high water normal cell line COS7 and cancer cell lines HepG2 and A549. A content. Protease/redox/pH stimuli-responsive PEGylated poly variety of innovative semi-interpenetrating polymer network (methacrylic acid) PMAA nanohydrogels have been synthesized (semi-IPN) hydrogels consisting of salecan and poly(methacrylic using cystamine as crosslinker for targeted anticancer drug acid) (PMAA) are formed via free-radical polymerization for delivery . The cumulative release profile indicates greater release controlled drug delivery (Fig. 4a) . Drug release is facilitated in acidic media (pH ~ 5.0) and reducing environments (GSH). under acidic conditions as protonated PMAA disrupts the Intravital real-time fluorescence image analysis indicates the quick electrostatic interaction between DOX and the hydrogel (pH < accumulation and maintenance of FITC-labeled PMAA nanohy- 5.5), favoring drug release compared the conditions at to pH ~ 7.0 drogels in the kidney, liver, and other organs, such as the heart, (Fig. 4b). Due to this factor, pH ~ 5 is considered representative of lung, and spleen; after 30 min of administration, extended in vivo simulated cancer environments. Successive exposure to a different blood circulation lifetimes have been shown using PEGylated FITC- release media at pH 7.4 and 5.0 causes pH-dependent ‘off-on’ labeled PMAA nanohydrogels (Fig. 4d). Yang et al. prepared switching of drug release. Cellular uptake of DOX released from poly(N-isopropylacrylamide)-ss-acrylic acid (P(NIPAM-ss-AA)) nano- drug-loaded hydrogels has effectively been shown in A549 and gels based on NIPAM and AA crosslinked by N,Nʹ-bis(acryloyl) HepG2 cells, showing great promise for hydrogels to be utilized as cystamine (BAC) through precipitation polymerization, which a vehicle for anticancer drug delivery (Fig. 4c). Poly(vinyl exhibited pH/redox dual-responsive DOX release in vitro and in pyrrolidone) stabilized fluorescent red copper nanoclusters can tumor cells. Animal studies have demonstrated the efficient be converted into hydrogel nanocarriers through crosslinking with penetration of DOX-loaded nanogels with fewer side effects, poly(vinyl alcohol) to deliver the anticancer drug cisplatin (CP) to indicating a prospective platform for intracellular controlled drug cervical cancer cells (HeLa), thereby inducing apoptotic cell release in cancer therapy. Bovine serum albumin (BSA) and death . The high encapsulating efficiency is attributed to chitosan (CS) nanogels prepared via a green self-assembly 128,129 molecule loading on the surface and inside the hydrogel particle, technique exhibit slow release with lower cytotoxicity . followed by strong interactions using various functionalities, such Biocompatible and pH-responsive self-assembled nanogels of as −COOH. The slow release of CP at physiological pH is due to chitosan-graft-poly(N-isopropylacrylamide) have been used as a stronger bonding between the drug molecule and the hydrogel, model tumor-targeting delivery system and had greater activity in which can be disrupted at acidic pH, favoring fast release. The acidic media . Alginate-PAMAM dendrimer-based hybrid nano- significant decrease in cell viability in the presence of drug-loaded gels have been developed for drug delivery to cancer cells, and carriers as opposed to free drug molecules reveals the combina- they showed pH-dependent release behavior in a sustained tion of Cu NC−hydrogel composites and CP as a potential material way . Nanocarriers have been found to release more drug in for the design of new chemotherapeutic agents. Doxorubicin acidic environments (mimicking tumor microenvironments) than loaded poly(methacrylic acid) (PMAA) hydrogel cubes and spheres in physiological conditions. are capable of both intracellular degradation and pH- Nanotechnology is a rapidly growing research area in the field responsiveness by introducing cystamine crosslinks within net- of catalysts, biosensors, bioimaging, energy devices, and targeted 114 132–134 works . The membrane adhesion process in the initial step of drug delivery . The large surface-to-volume ratio of nano- cell internalization is greatly affected by the shape of the particles, particles and their size, ability to carry other compounds, binding and hydrogel spheres exhibit 12% higher cell cytotoxicity than ability and their adsorption properties make them suitable for cubes using HeLa cells for 10 h. Shape and pH-sensitive biomedical applications. Nanoparticles can also improve bioavail- ‘intelligent’ 3D networks with programmable shape-regulating ability, protect drugs from degradation and control release rates, behaviors are promising candidates for the controlled delivery of i.e., provide sustained drug release. These unique characteristics of chemotherapeutics. Doxorubicin encapsulated poly(vinylcaprolac- nanoparticles offer a viable platform for their use as an effective tam) (PVCL)-based biodegradable microgels have been designed drug delivery system . Biodegradable carboxymethyl cellulose/ for stimuli-triggered drug release in acidic or reducing environ- graphene oxide (CMC/GO) nanohybrid hydrogel beads physically ments . DOX-loaded microgels exhibit efficient antitumor crosslink with FeCl .6H O have been used for the controlled 3 2 activity to HeLa cells against nontoxic blank microgels. Supramo- release of an anticancer drug (DOX) . The π–π stacking lecular hybrid hydrogels of α-cyclodextrin and polyethylene interaction between GO and DOX caused higher drug loading modified gold nanocrystals exhibit pH-dependent sustained efficiency. The release profile from hydrogels was highly pH- release of DOX through host–guest interaction . Tetrapeptide- dependent, based on hydrogen bonded interactions and exhib- based thermoreversible, pH-sensitive hydrogels have been ited a faster release at pH ~ 6.8 than in slightly basic media (pH ~ prepared for the slow release of anticancer drugs at physiological 7.4). Furthermore, greater amounts of filler/GO reduced the pH . Hexamethylene diisocyanate (HDI) reacts with Pluronic release rate because of enhanced interactions between the F127 as a chain extender to form a copolymer, and subsequent components. Halloysite nanotubes embedded hybrid hydrogels incorporation of hyaluronic acid (HA) has been used to develop a of poly(hydroxyethyl methacrylate) with sodium hyaluronate were composite hydrogel system with a sol–gel transition at 37 °C, very effective for colon cancer drug delivery . Anticancer drugs, leading to the formation of a nanocomposite injectable hydrogel such as 5-fluorouracil (5-FU), have been encapsulated not only in for drug delivery with controlled release . hydrogel networks but also in halloysite nanotubes using an equilibrium swelling method, followed by pulling and breaking Hybrid materials for controlled drug delivery the vacuum. In vitro release of 5-FU from nanohybrid hydrogels Nanoscale dimension hydrogel particles are often called ‘nano- exhibited pH-dependent controlled release following diffusion- gels’ and are formulated either by physically or chemically controlled non-Fickian transport behavior. 5-FU was also inter- 10,119 crosslinked hydrophilic polymers . Nanogels have been calated within the gallery of natural montmorillonite (Mt) clay, recently exploited in various fields, including diagnostics, chemical which could be compounded using alginate (Alg), followed by a and biochemical sensing, tissue engineering, and cancer imaging, coating with chitosan (CS), to prepare a complex drug release 120–123 138 especially as drug delivery vehicle . Nanogels offer several system with controlled release behavior . The release rate of 5- advantages in therapeutic delivery in comparison to existing FU was found to be retarded when using an Alg–CS/5-FU/Mt nanocarriers: (i) high drug loading capacity; (ii) higher storage nanohybrid system in gastric and intestinal environments. Hybrids stability than liposomes and micelles; (iii) controlled and sustained of nanoclay and chitosan–polylactide blends also released Signal Transduction and Targeted Therapy (2018) 3:7 Drug Delivery Vehicles for Cancer Treatment Senapati et al. Fig. 5 Stimuli-responsive targeted delivery of therapeutic agents. a Schematic illustration of stimuli-responsive DDS; b Schematic diagram of pH and GSH dual-responsive dynamic crosslinked supramolecular network on MSN-SS-(EDA-PGOHMA) and synthetic route with CB assembly; c Design of temperature-sensitive liposomes composed of thermosensitive poly(EOEOVE)-OD4 (i), membrane-forming EYPC (ii), membrane-stabilizing cholesterol (iii), and highly hydrophilic and nontoxic PEG-lipid (iv). Heat-triggered release of DOX from liposomes is illustrated with the structure of poly(EOEOVE)-OD4 paclitaxel in a pronounced manner in basic conditions compared antibacterial smart polymer nanohybrids have the potential to be their release in acidic environments . Biodegradable poly(ε- used for combination cancer therapy. caprolactone)nanohybrid scaffolds with organically modified nanoclay, which were prepared through an electrospinning technique, exhibited sustained delivery of an anticancer drug TARGETED DELIVERY: MECHANISTIC PATHWAY (dexamethasone) vis-à-vis pure polymer by creating a maze or Target-specific deliveries of therapeutic agents are based on ‘tortuous path’ that retarded the diffusion of the drug from the stimuli-responsive factors induced by either endogenous (pH, matrix in the presence of a two-dimensional filler . Biocompa- redox, enzyme) or exogenous stimuli (temperature, acoustic, light) tible polyurethane nanohybrids using an aliphatic diisocyanate as shown in Fig. 5a . pH-sensitive chitosan-based supramole- and aliphatic chain extender with varying chain lengths and 2D cular gel is used for oral drug delivery of insulin. The pH sensitivity nanoclay was designed for sustained drug delivery of an of the nanogel protects insulin while it is in the stomach, and the anticancer drug in which the tortuous path was created through bioadhesivity of chitosan enables prolonged contact with the 141 151 larger crystallites from self-assembly of a hard segmented zone . intestinal mucosae to increase the absorption of insulin . The Graphene-based polyurethane nanohybrids have been prepared drug delivery platform based on mechanized silica nanoparticles by grafting long chain polyurethane onto the surface of (MSNPs), which consists of MSNs vehicles, acid-cleavage inter- functionalized graphene oxide for sustained drug delivery of an mediate linkages and reversible supramolecular nanovalves, was anticancer drug (dexamethasone) . Chemically tagged amine- devised to achieve multimodal controlled release of two drugs, and sulfonate-functionalized graphene within long chain poly- gemcitabine (GEM) and doxorubicin (DOX), by arranging the order urethane molecules has been developed for the sustained release of stimuli in sequence. The release time and dosage of GEM are 143,144 of dexamethasone . A hard segment in pure polyurethane precisely controlled via external voltage, whereas subsequent acid was responsible for delayed drug release, whereas the self- treatment triggers the release of DOX, which is attributed to assembled structure and graphene moieties acted as a barrier for breakage of the intermediate linkages containing ketal groups . the diffusion of loaded drugs in nanohybrids. Several other Dynamic crosslinked supramolecular networks of poly(glycidyl polymer nanoparticle hybrid systems have been reported as methacrylate) derivative chains on mesoporous silica nanoparti- sustained release systems for cancer therapy using different drugs, cles respond well against the dual stimuli of pH and glutathione- 145–149 such as DOX, 5-FU, and MTX . The dual-administration of (GSH-) linkage, which control the release of anticancer drug DOX with MTX had higher cytotoxicity towards T47D breast cancer doxorubicin hydrochloride (DOX) under a simulated tumor cells than free dual drug forms. Dual anticancer drug-loaded intracellular environment (pH = 5.0, CGSH = 2~10 mM). Signal Transduction and Targeted Therapy (2018) 3:7 Drug Delivery Vehicles for Cancer Treatment Senapati et al. Disassembly of the crosslinked polymer network occurs by into tumor bearing mice, and tumor growth is significantly lowering the pH, and cleavage of disulfide bonds efficiently suppressed only when the tumor site is heated to 45 °C for 10 min 153 155 promotes drug release kinetics (Fig. 5b) . Glutathione disulfide after 6–12 h of injection (Fig. 5c) . Biocompatible poly(N-(2- (GSSG) is the oxidized form of glutathione (GSH), which is the hydroxypropyl-methacrylamide) (PHPMA) functionalized cyclodex- major endogenous antioxidant. Glutathione protects biological trin (CD) is the building block that houses two guests, e.g., poly(N, systems from oxidizing factors, such as reactive oxygen species, by N-dimethylacrylamide) (PDMAAm) and poly(N,N-diethylacryla- terminating them; GSH is oxidized to GSSG, and then it is reduced mide) (PDEAAm), prepared via reversible addition−fragmentation back to GSH by glutathione reductase (GR). The unique antimeta- chain transfer (RAFT) polymerization and can form a well-defined static mechanism of glutathione disulfide (GSSG) based liposomes supramolecular ABA triblock copolymer responsive to UV light and completely prevents cell detachment and migration and sig- temperature. CD-based host/guest complexes show thermore- nificantly inhibits cancer cell invasion and has been confirmed as a sponsivity due to the negative enthalpy of complex formation. The potential treatment for cancer metastasis . Temperature- application of these stimuli leads to the disassembly of the triblock sensitive liposomes with temperature-sensitive amphiphilic poly- copolymer, which has been shown to be reversible, and is mer poly(EOEOVE)-OD4 are used for tumor-specific chemother- ultimately responsible for regulated delivery. In case of PDEAAm, apy. DOX encapsulated liposomes are administered intravenously temperature-induced aggregation is observed after heating above Fig. 6 Reslease and cellular uptake of drug using magnetic nanoparticles under magnetic field. a Schematic representation of a four armed PE −PCL immobilized magnetic nanoparticle (MNP); b Schematic representation of DOX-loaded MNP and DOX release under the influence of high field alternating magnetic field (HFAMF); c The release kinetics of MNP 3 (particle size of 3 nm) and MNP 5 (particle size of 5 nm) under the influence of HFAMF at 37 °C; d Cellular uptake study of DOX-loaded MAPM on HeLa cell in the presence of a static magnetic field where the nucleus was stained by DAPI (blue) . The scale bar is 40 μm Signal Transduction and Targeted Therapy (2018) 3:7 Drug Delivery Vehicles for Cancer Treatment Senapati et al. Fig. 7 Electric field guided control release of drug. a General scheme for the application of this system: (i) the nanoparticle-polymer solution is (ii) subcutaneously injected into a mouse, followed by (iii) application of a DC electric field to induce the release of drug cargo inside the nanoparticles; b Released amount of daunorubicin in PBS (pH 7.2) following an applied voltage (0.5 V) duration of 10 s, repeated every 5 min the cloud point of the PDEAAm block . Tripeptide Lys–Phe–Gly DOX into the nanoparticle and its release under the influence (KFG), a biologically important tripeptide, is spontaneously self- of high frequency alternating magnetic fields is schematically assembled into well-defined nanostructures in aqueous media, shown in Fig. 6b. The release profiles at the two different showing an exciting phenomenon of reversible and concentration temperatures are not remarkable, whereas drug release is dependent switching of nanostructures between nanovesicles and considerable (51.5%) under the influence of a magnetic field for nanotubes as evidenced by dynamic light scattering, transmission 1 h (Fig. 6c) as the self-assembled structure ruptures under a electron microscopy and atomic force microscopy studies. The strong magnetic field. This form of magnetically controlled DOX tripeptide vesicles have inner aqueous compartments and are release is quite advanced in magnetically active polymeric stable at pH 7.4, but they rupture rapidly at pH 6. The pH-sensitive micelles and is superior from a patient compliance viewpoint response of the vesicles is exploited for delivery of a chemother- compared to other conventional methods used for drug delivery apeutic anticancer drug (doxorubicin), resulting in enhanced (diffusion, pH, thermal response, etc.). The efficacy of magnetic cytotoxicity for both drug-sensitive and drug-resistant cells. The fields for drug release is indicated by effective intercellular uptake absence of the KFG sequence in the receptor polypeptide chain of after only 0.5 h of incubation in the presence of a magnetic field tyrosine kinase nerve growth factor (Trk NGF) strongly affects the with no incorporation of the drug in absence of the field (Fig. 6d). activation of signaling cascades. Efficient intracellular release of A magnetically driven paclitaxel delivery system has been the drug is confirmed by fluorescence-activated cell sorting designed by incorporating iron oxide and a drug in a palmitoyl analysis, fluorescence microscopy, and confocal microscopy .A chitosan matrix through a nanoprecipitation method for con- combination of an aptamer for target recognition and enzyme trolled drug delivery under magnetic field . Enhanced cell (MCF- phosphatidylcholine 2-acetylhydrolase (PLA2) for rupture of lipid 7) death occurs due to the hyperthermic effects of magnetic bilayer of liposomes containing uranin and gadopentetic acid nanoparticles in the presence of an external magnetic field, (GdDTPA) as signaling agents have been investigated for resulting in a biocompatible and biodegradable carrier for the fluorescence and MRI detection. Thus, aptamer−PLA2 triggers precise delivery of powerful cytotoxic anticancer agents. A the release mechanism via the target-responsive liposome system dramatic change in the amount of drug release is found when for signal transduction and selective recognition of biological the remote magnetic field is switched ‘on’ and ‘off’ using silica molecules . magnetic nanocapsules containing camptothecin (hydrophobic) and doxorubicin (hydrophilic) in drug enriched areas near mouse Magnetic field for cancer treatment breast tumors, and the nanocapsules are effective at reducing Magnetic (micro- or nanoparticles) materials were explored a tumor cell growth . Magnetic carriers for drug delivery using couple of decades ago as potential carriers for specific drug superparamagnetic nickel ferrite nanoparticles functionalized with targeting. External magnetic fieldscan be used as a responsive poly(vinyl alcohol), poly(ethylene oxide) and poly(methacrylic drug delivery system to transport drugs to tumor sites. Recently, acid) (PMAA) and subsequently conjugated with doxorubicin superparamagnetic Fe O magnetic nanoparticles have been anticancer drug have significantly enhanced the release rate 3 4 synthesized through grafting using four armed pentaerythretol under magnetic fields by creating mechanical deformation, which poly(ε-caprolactone) in the form of micelles for magnetically generates compressive and tensile stresses to eject drug 159 162 targeted controlled drug (DOX) delivery (Fig. 6a) . The loading of molecules . Signal Transduction and Targeted Therapy (2018) 3:7 Drug Delivery Vehicles for Cancer Treatment Senapati et al. Fig. 8 Laser guided control drug delivery using MoS for cancer treatment. a Schematic illustration of high-throughput synthesis of MoS -CS 2 2 nanosheets as an NIR photothermal-triggered drug delivery system for efficient cancer therapy. (i, ii) Oleum treatment exfoliation process to produce single-layer MoS nanosheets that are then modified with CS, (iii) DOX loading process, and (iv) NIR photothermal-triggered drug delivery of the MoS nanosheets to the tumor site. b Release profile of DOX in PBS buffer (pH 5.00) in the absence and presence of an 808-nm NIR laser. c Fluorescence images of KB cells treated with free DOX, MoS -CS-DOX, and MoS -CS-DOX under 808-nm NIR irradiation (inset: high 2 2 magnification of the rectangle area) Electric field for cancer therapy graphene oxide composite with a polypyrrole scaffold that had a Attention is being given to stimuli-responsive or ‘smart’ biomater- linear release profile under the influence of voltage stimulation, 163–167 ials in the fields of biotechnology and biomedicine . Stimuli- and dosages were adjusted by altering the magnitude of the 168,169 170,171 responsive materials, which respond to heat ,pH , stimulation, proving on-demand drug delivery. Carbon nanotubes 172,173 174,175 176,177 light , enzymes , and magnetic fields , are widely (CNTs) can act as drug nanoreservoirs by holding drug molecules used in the biomedical arena. Electrical signals are easier to within their inner cavity, releasing them in bioactive form under generate and control than other stimuli. Electric stimuli have electrical stimulations . A polypyrrole coating over CNT drug successfully been utilized to trigger the release of molecules via nanoreservoirs seals the ends of the CNTs, effectively loading the conductive polymeric bulk materials or implantable electronic drug, which allows electrical triggering to release the drug with delivery devices. Drug release systems based on conductive the application of voltage . A dual stimuli (electric field and pH) polymers have successfully been utilized, as they offer the responsive system of chitosan–gold nanocomposites (CGNC) has possibility of drug administration through electrical stimulation. been designed for site specific controlled delivery of the Ge et al. designed an electric field responsive drug delivery anticancer drug 5-FU at the reduced pH of cancer cell system using nanoparticles of the conductive polymer polypyr- environments . role. Polypyrrole nanoparticles serve as a drug reservoir for electric field triggered release when they are embedded in biocompatible Thermal treatment for cancer therapy and biodegradable hydrogels of poly[(D,L-lactic acid)-co-(glycolic Photodynamic therapy is an advanced approach that offers acid)]-b-poly(ethylene oxide)-b-poly-[(D,L-lactic acid)-co-(glycolic control of drug delivery through the use of an external photon acid)] (PLGA-PEG-PLGA) (Fig. 7a). This gel is injectable (solution source to provide active therapeutic release to a targeted area. at low temperature but converts into a gel at body temperature) Chitosan-functionalized MoS (MoS -CS) nanosheets can act as a 2 2 and upon application of an external DC electric field, it releases chemotherapeutic drug nanocarrier for near-infrared (NIR) the drug from the nanogel, allowing the drug to diffuse into the photothermal-triggered drug delivery systems, facilitating the surroundings from the hydrogel. Each electric stimulus releases combination of chemotherapy and photothermal treatment for ~25 ng of drug into the solution (Fig. 7b) with minimal release in cancer therapy . The synthesis procedure of single-layer MoS the absence of an electric field, indicating undesired release from nanosheets and NIR-triggered drug release from MoS nanocar- the hydrogel. This type of delivery system has great advantages riers for cancer therapy are shown in Fig. 8a. Drug release profiles over conventional sustained drug release because the released show a sharp increase upon irradiation with NIR laser followed by dose of this drug can be roughly controlled by either the strength power-dependent release and show nonsignificant release in the or the duration of the electric field. Electrically controlled drug absence of irradiation (Fig. 8b). MoS -CS plays an important role in delivery has been demonstrated by Weaver et al. , who used a regulating the release of DOX molecules and enhances their Signal Transduction and Targeted Therapy (2018) 3:7 Drug Delivery Vehicles for Cancer Treatment Senapati et al. nuclear accumulation under NIR irradiation (Fig. 8c). Effective ahead to monitor the mortality rate due to cancer. Most of treatment of pancreatic cancer in vivo under NIR irradiation has these carriers have been designed and tested in small been carried out, confirming the synergistic efficacy of hyperther- animal models, achieving great therapeutic results; however, the mia and chemotherapy. This kind of nanocarrier offers a new translation of animal results into clinical success has been possibility for better ‘on-demand’ drug delivery systems that can limited. More clinical data are needed to fully understand the enhance antitumor efficacy. Dual-in-dual synergistic therapy advantages and disadvantages of these vehicles. Now, we have based on the use of dual anticancer drug-loaded graphene oxide entered into an era of molecular targeting of cancer that may (GO) stabilized with poloxamer 188 has been developed to further improve the chemotherapeutic index by detecting generate heat and deliver drugs to kill cancer cells under near- malignant cells (active targeting moiety), tracking their location infrared (NIR) laser irradiation . Dual drug (doxorubicin and in the body (real-time in vivo imaging), killing cancer cells irinotecan)-loaded GO (GO-DI) in combination with laser irradia- while producing minimal adverse side effects by sparing tion caused higher cytotoxicity than that caused by the normal cells (active targeting and controlled drug release or administration of a free single drug or a combination of drugs hyperthermia ablation) and monitoring the study in real-time. Ion and blank GO in various cancer cells, especially in MDA-MB-231 beam therapy seems to be a promising tool for oncologists to resistant breast cancer cells, suggesting that GO-DI is a powerful treat cancer in near the future instead of high-risk surgery, tool for drug delivery and can achieve improved therapeutic widespread damage from other forms of radiation therapy, such efficacy and overcome drug resistance in combined chemopho- as X-rays, or collateral damage induced by chemotherapeutic tothermal therapy. A photoactivatable o-nitrobenzyl (ONB) deri- drugs. Classic radiation treatment involves mainly X-rays, which vative of 5-fluorouracil (5-FU) attached to the surface of lose energy all along their path through the body and thereby upconverting nanoparticles served as a photocaging nanocarrier damage healthy cells in their path. The beams of protons that absorbed NIR radiation with upconversion in the UV range, or heavier ions, such as carbon and neon, can be accelerated which triggers cleavage of the bonds between ONB-FU at the precisely with calculated energy to accurately target tumor cells, nanoparticle interface to release chemotherapeutic 5-fluorouracil sparing healthy tissue above and below the targeted site. (5-FU) . The main advantage of employing ion beam radiation for cancer The efficiency of triggered release is sufficiently high (77%) treatment is that it has the potential to precisely target any type or for the total ONB−FU conjugate, whereas the rate of drug release form of tumor, which may be very small or large and may be can be tuned with laser power output. The development dangerously shaped or positioned surrounding the spinal cord, in of this type of UCNP provides a valuable platform for targeted the center of the brain or close to the optic nerves. Even though chemotherapy. Thermoresponsive micelles using an amphiphilic proton therapy is commonly used at present, heavier carbon diblock copolymer, poly{γ-2-[2-(2-methoxyethoxy)-ethoxy]ethoxy- ions deposit more energy in tumor tissues. Therefore, ε-caprolactone}-b-poly(γ-octyloxy-ε-caprolactone), display a low carbon or other heavier elements are considerably more critical solution temperature (LCST) of 38 °C and can release the destructive towards the tumor, and hence, they require a fewer therapeutic agent in a controlled fashion . When the anticancer number of doses for treatment. For example, liver cancer requires drug doxorubicin is loaded into the micelle, the micelles exhibit 30 days of treatment using proton therapy, whereas only just four statistically higher cytotoxicity against MCF-7 cells at temperatures days of treatment is sufficient for carbon therapy. Carbon above the LCST. β-cyclodextrin-poly(N-isopropylacrylamide) star therapy provides the highest linear energy transfer (LET) of any polymer is able to form a supramolecular self-assembled inclusion currently available form of clinical radiation. This high energy irradiation to tumor cells results in the destruction of most complex with PTX via host–guest interactions at room tempera- ture, which is below the lower critical solution temperature of the double-stranded DNA; this extensive destruction is very difficult star polymer and significantly improves the solubilization of for other conventional radiation therapies to accomplish, PTX . Phase transitions of poly(N-isopropylacrylamide) segments as they predominantly break single-stranded DNA. Recent at body temperature (above LCST) induce the formation of technological advancements in the fields of accelerator nanoparticles, which greatly enhance cellular uptake of the engineering, beam delivery, treatment planning, and tumor polymer–drug complex, resulting in efficient thermoresponsive visualization have transferred ion beam therapy from physics delivery of PTX. Dual pH/light-responsive crosslinked polymeric laboratories to clinics. micelles (CPM), prepared by the self-assembly of amphiphilic glycol chitosan-o-nitrobenzyl succinate conjugates (GC-NBSCs) and then crosslinked using glutaraldehyde (GA), are used as a drug carrier that can release drugs quickly at low pH under light CONCLUSIONS irradiation . Thus, GC-NBSC CPMs provide a favorable platform This review has summarized a variety of materials that are either to construct dual pH/light-responsive smart drug delivery systems being used or have the potential to be used as drug delivery (DDS) for cancer therapy. Biodegradable plasmon resonant vehicles for the treatment of cancer. Their unique attributes have liposome gold nanoparticles, which are synthesized using 1,2- allowed clinicians to offer them as new treatments (monotherapy) distearoyl-sn-glycero-3-phosphocholine (DSPC)-cholesterol coat- or as adjuncts to existing treatments (combined therapy) to ing with gold nanoparticles, are capable of killing cancer cells improve therapeutic effectiveness. Although some of these through photothermal therapy. materials have not been successful upon their clinical translation, several new and promising materials that are currently under Future challenges in cancer therapy development show great promise, thereby providing hope for Novel drug delivery systems promise a bright future for cancer new treatment options in the near future. treatment in the next decade or so; they might become major arsenal for safer and more efficient treatments by ensuring proper drug localization at the site of action in a controlled manner. The enhanced therapeutic efficacy of targeted nanocarriers has been ACKNOWLEDGEMENTS Research fellowships from UGC (New Delhi, India) (S.S.) and CSIR (New Delhi, India) (A. established in cancer treatment using multiple animal models that K.M.) are gratefully acknowledged. We also acknowledge the Science and target tumors and deliver drugs for targeted radiotherapy, 189,190 Engineering Research Board (Grant No: R&D/SERB/LT/SMST/16/17/06) (SERB) New imaging-guided radiotherapy and precision medicine . Delhi for financial support. We also acknowledge the Council for Scientific and Although major advances have been made by current drug Industrial Research (Grant No. 02(0074)/12/EMR-II) (CSIR-UGC), New Delhi. delivery systems in the treatment of most cancers, much work lies Signal Transduction and Targeted Therapy (2018) 3:7 Drug Delivery Vehicles for Cancer Treatment Senapati et al. ADDITIONAL INFORMATION 29. Lin, Y. et al. Advances toward bioapplications of carbon nanotubes. J. Mater. Conflict of interest: The authors declare that they have no conflict of interest. Chem. 14, 527–541 (2004). 30. Bianco, A., Kostarelos, K. & Prato, M. Applications of carbon nanotubes in drug delivery. Curr. Opin. Chem. Biol. 9, 674–679 (2005). 31. Fadel, T. R. & Fahmy, T. 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