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Sol–Gel Treatment of Textiles for the Entrapping of an Antioxidant/Anti-Inflammatory Molecule: Functional Coating Morphological Characterization and Drug Release Evaluation

Sol–Gel Treatment of Textiles for the Entrapping of an Antioxidant/Anti-Inflammatory Molecule:... applied sciences Article Sol–Gel Treatment of Textiles for the Entrapping of an Antioxidant/Anti-Inflammatory Molecule: Functional Coating Morphological Characterization and Drug Release Evaluation 1 2 3 1 Francesco Puoci , Carmela Saturnino , Valentina Trovato , Domenico Iacopetta , 4 5 2 6 Elpida Piperopoulos , Claudia Triolo , Maria Grazia Bonomo , Dario Drommi , 1 4 1 , 3 , Ortensia Ilaria Parisi , Candida Milone , Maria Stefania Sinicropi * , Giuseppe Rosace * 7 , and Maria Rosaria Plutino * Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Via Pietro Bucci, 87036 Arcavacata di Rende (CS), Italy; francesco.puoci@unical.it (F.P.); domenico.iacopetta@unical.it (D.I.); ortensiailaria.parisi@unical.it (O.I.P.) Department of Science, University of Basilicata, Viale dell’Ateneo Lucano 10, 85100 Potenza, Italy; carmela.saturnino@unibas.it (C.S.); mariagrazia.bonomo@unibas.it (M.G.B.) Department of Engineering and Applied Sciences, University of Bergamo, Viale Marconi 5, 24044 Dalmine (BG), Italy; valentina.trovato@unibg.it Department of Engineering, University of Messina, Contrada di Dio, S.Agata, 98166 Messina (ME), Italy; epiperopoulos@unime.it (E.P.); candida.milone@unime.it (C.M.) Department of Mathematics and Computer science, Physical and Earth Sciences, University of Messina, Viale F. Stagno d’Alcontres 31, Vill. S. Agata, 98166 Messina (ME), Italy; claudia.triolo@unime.it Department of ChiBioFarAm, University of Messina, Viale F. Stagno d’Alcontres 31, Vill. S. Agata, 98166 Messina (ME), Italy; ddrommi@unime.it Institute for the Study of Nanostructured Materials, ISMN—CNR, Palermo, c/o Department of ChiBioFarAm, University of Messina, Viale F. Stagno d’Alcontres 31, Vill. S. Agata, 98166 Messina (ME), Italy * Correspondence: s.sinicropi@unical.it (M.S.S.); giuseppe.rosace@unibg.it (G.R.); mariarosaria.plutino@cnr.it (M.R.P.); Tel.: +39-0984-493200 (M.S.S.); +39-035-2052021 (G.R.); +39-090-6765713 (M.R.P.) Received: 13 February 2020; Accepted: 20 March 2020; Published: 27 March 2020 Abstract: The growing interest towards textile-based drug delivery systems is due to their potential innovative medical and well-being applications. In recent years, the technique of encapsulation or inclusion of the medicine/active principle into a polymer functional matrix has been employed in order to obtain textile materials with controlled drug release. In this study, a sol–gel-based coating was developed and used as an entrapping polymeric cross-linked network for a N-Palmitoyl-ethanolamine (PEA) derivative, 2-methyl-pentadecanoic acid (4-nitro-phenyl)-amide or N-Palmitoyl-(4-nitro-phenyl)-amine (PNPA), whose anti-inflammatory and antioxidant properties have already been shown. A wide series of chemical-physical methods have been used to characterize the silica-based functional sol and to ascertain the ecient and temporary deposit of PNPA on the sol–gel coated cotton fabrics. The medicine release system achieved was shown to ensure biocompatibility, PNPA reservoir and its subsequent releasing under the action of cutaneous stimuli, thus providing useful insights in the design of medical textiles. Keywords: sol–gel coating; medical textiles; antioxidant; anti-inflammatory; PEA derivative; drug release 1. Introduction The research field dealing with the development of controlled drug delivery systems has been of relevant scientific interest since the 1970s and has grown and diversified rapidly in recent years, in Appl. Sci. 2020, 10, 2287; doi:10.3390/app10072287 www.mdpi.com/journal/applsci Appl. Sci. 2020, 10, 2287 2 of 13 particular thanks to the benefits it brings to healthcare; furthermore, it covers a large market segment [1]. In general, the e ectiveness of drug therapy is the main objective of controlled release systems [1,2], with a corresponding (i) reduction of the number of drug administrations; (ii) improvement in therapeutic activity [3,4]; (iii) consequent reduction of the intensity of side e ects; and (iv) elimination of specialized drug administration [5]. This pharmaceutical technology, especially in recent years, has seen application in other fields ranging from cosmetics [6] to agriculture [7], including textiles [8,9], as an interesting and innovative application. Indeed, textile fabrics, thanks to their biocompatibility, breathing structure and absorptive capacity, are of great interest as a medium (for ex vivo applications) for controlled release of drugs, active principles or aroma substances of particular comfortability [10]. Several examples are nowadays in common use, such as the well-known transdermal patches or textile costumes, generally characterized by di erent layers in which the release of a specific drug substance, deposited on the textile surface, is activated by stimuli such as temperature, humidity, enzyme, perspiration types or friction [11]. In general, in controlled release systems, biocompatibility and controllability are important features; furthermore, in terms of biocompatibility, the carcinogenicity, toxicity, teratogenicity and mutagenicity are important elements to be controlled [10]. The use of textile fabrics for the realization of controlled release systems presents several advantages but on the other hand, some disadvantages with respect to the oral administration of substances. Indeed, this administration represents an attractive and easier therapy for the patient due to its ecacy since the drug avoids both the digestive apparatus and the hepatic metabolism that reduce the concentration of the drug. Furthermore, it requires lower dosages due to the higher di usion through tissues, which correspond to lower social costs of therapies [11]. On the other hand, the disadvantages are related to the di usion rate of the drug as function of its molecular structure and body surface administration [11]. Di erent methods have been employed in order to develop better textile-based delivery systems (i.e., bandages, patches), with good controllability, biocompatibility and active species entrapment/release by use of host-guest molecules (cyclodextrins [12], aza-crown ethers, fullerenes) or doping functional molecules (ion-exchange; drug-loaded hollow; nanoparticles; bioactive) [10]. Several C–C polymer heteroatom-containing (i.e., N, P, Si) backbones for controlled release applications have been tested and considered in order to improve the drug therapy e ectiveness [5]. All the developed release polymeric systems have been shown to act through mechanisms of temporal controlled release, such as drug-delayed dissolution, di usion-controlled, and drug solution flow control after interaction with environmental water or by reacting to specific skin stimuli. The sol–gel method has been shown to be a useful method in the preparation of functional nanostructured coatings for textiles, thus combining the entrapment/encapsulation of bioactive compounds, biomolecules and their controlled release [13]. In our previous studies, we have already shown that nano-hybrid sol–gel-based coatings feature abrasion resistance, tensile strength and elongation properties of the treated fabrics [13,14]. These peculiar characteristics may be combined with a proper doping molecule, such as a dye [15–21], an antimicrobial [22], a hydrophobic [23–25] or a flame-resistant molecule [26,27], with the aim of improving the textile surface properties and making a functional nano-hybrid coating. With the aim of developing a functional sol–gel-based coating suitable for medical application, we thought worthwhile to make a silica sol containing the 3-glycidoxypropyltriethoxysilane (GPTES, hereafter “G”), as silica cross-linker precursor, and a PEA derivative, the N-Palmitoyl-(4-nitro-phenyl)-amine (hereafter PNPA), whose anti-inflammatory and antioxidant properties have already been tested and compared with other analogue molecules [28]. The sol was successfully applied on cotton surfaces and, after drying and curing, a stable and uniform PNPA-containing silica-based coating was obtained, as confirmed by morphological studies (SEM and AFM microscopy). As already shown in previous studies for halochromic dyestu [20], the PEA derivative results firmly encapsulated into the 3D hybrid silica layer in absence of external stimuli (i.e., variable pH conditions), thanks to non-covalent and weak interactions (i.e., hydrogen bonds Appl. Sci. 2020, 10, 2287 3 of 13 and van der Waals interactions) acting between the non-polar active molecule and the alkoxysilane hosting network. Finally, the functionally coated cotton samples were employed for in vitro di usion studies with the aim of testing their ability to release the synthesized PEA derivative in a controlled manner compared to a standard solution of the molecule. This e ectively prepared functional hybrid system, based on the non-covalently immobilized PNPA, showed good results so that it can be considered a suitable sca old for fabrics in drug release applications, thus providing useful insights in the design and the development of medical textiles. 2. Materials and Methods N-Palmitoyl-(4-nitro-phenyl)-amine (PNPA) was synthetized according to a synthetic strategy described in previous researches [28]. 3-glycidyloxypropyltriethoxysilane (GPTES) and methanol were purchased from Wacker and Aldrich, respectively, and used without further purification. Two cotton scoured and bleached 100% plain-weave textile fabrics (coded CO and CO ) kindly supplied by L H Albini S.p.A. (Albino, Italy) and Mascioni S.p.A. (Cuvio, Italy), respectively, were used for this research. 2 2 The fabrics showed di erent mass per unit area (CO = 119 g/m and CO = 331 g/m , respectively). L H Cotton fabrics were washed before treatment at pH 7 and at 40 C for 20 min in a non-ionic detergent, rinsed several times with de-ionized water and then dried. The cleaned samples were conditioned at 20 ( 1) C and under standard atmospheric pressure at 65 ( 2)% relative humidity for at least 24 h prior to all experiments. PNPA (25 mg) was dissolved in 40 mL of methanol through ultrasonication and left under continuous stirring. Then 2 mL of a 1 M aqueous sol–gel solution of GPTES were added drop by drop to the clear methanol solution of antioxidant molecule, thus resulting in a final GPTES sol concentration of 0.05 M (1:0.034 molar ratio with respect to PNPA). The obtained solution (G-PNPA sol) was ultrasonicated and left at room temperature under stirring for at least 90 min. The same reaction was also carried out in absence of the antioxidant molecule in order to obtain a reference GPTES sol sample. Both solutions were applied separately onto cotton textile (10 cm  10 cm) through a two-roll laboratory padder (Werner Mathis, Zurich, Switzerland) at a nip pressure of 2 bar, then dried (80 C for 5 min) and cured (100 C for 1 min) in an electric laboratory oven. PNPA, G-PNPA and G sols were fully investigated through FT-IR spectroscopy and Nuclear magnetic resonance (NMR). Untreated and treated textiles were characterized by FT-IR spectroscopy, Scanning Electron Microscopy (SEM) coupled to energy dispersive X-ray (EDS) and Atomic Force Microscopy (AFM). The PNPA controlled release from the two prepared textiles, CO _G-PNPA and CO _G-PNPA, L H was investigated by performing in vitro di usion studies using Franz di usion cells and according to the experimental protocol reported in a previous work [29]. For this purpose, Strat-M membranes (25 mm discs, Cat. No. SKBM02560, Merck Millipore, Darmstadt, Germany) were positioned between the donor and the receptor compartments of each Franz cell and the experiments were carried out at 37  0.5 C. The two tested items, CO _G-PNPA and CO _G-PNPA, were placed on L H the Strat-M membrane with the GPTES layer facing towards the acceptor chamber. Then, the Franz cell compartments were fixed together and filled with 0.5 and 5.5 mL of phosphate bu er at pH 7.4 (10 M), respectively. The content of the receptor chamber was withdrawn at di erent times, such as 1, 2, 4, 6 and 24 h, for UV-Vis analysis and replaced with phosphate bu er. The same experimental conditions were applied to a control sample consisting of a standard PNPA solution. The in vitro di usion studies were carried out in triplicate and the obtained results were expressed as di used amount (%). FT-IR spectra were performed by a Thermo Avatar 370 equipped with an attenuated total reflection (ATR) accessory and using a diamond crystal as internal reflectance element. Spectra were acquired 1 1 with 32 scans and in the range from 4000 to 550 cm with a resolution of 4 cm . Appl. Sci. 2020, 10, 2287 4 of 13 One- and two-dimensional NMR experiment were recorded in methanol-d at 298.2 (0.1) K on Bruker ARX-300, equipped with a 5 mm gradient probe and operating at 300.1 MHz for 1H nucleus. All chemical shifts are shown in parts per million (/ppm), downfield to tetramethylsilane (Me Si) as an internal standard ( = 0.0 ppm), or referenced to the residual protiated solvent 1 1 signal such as in methanol-d ( H NMR: 3.30 ppm). H NMR signals were assigned by means of two-dimensional Appl. Sci. 2020, 10, x FO homonuclear R PEER REVIEWNMR gradient experiments (gCOSY, gNOESY), acquir 4 of ed 13 using standard Bruker pulse sequences. 146 an internal standard (δ = 0.0 ppm), or referenced to the residual protiated solvent signal such as in SEM morphology and SEM-EDS of the investigated samples were obtained using a FEI Quanta 1 1 147 methanol-d4 ( H NMR: 3.30 ppm). H NMR signals were assigned by means of two-dimensional FEG 450 microscope. An operating voltage of 5 kV in low vacuum was used for SEM images. EDS 148 homonuclear NMR gradient experiments (gCOSY, gNOESY), acquired using standard Bruker pulse analysis was conducted with an operating voltage of 20 kV, always in low vacuum. Samples were 149 sequences. fixed on aluminum sample holders by means of a graphitic adhesive. 150 SEM morphology and SEM-EDS of the investigated samples were obtained using a FEI Quanta 151 AFM FEG 450 mic characterization roscope. An was operating performed voltage using of 5 a kV in low v stand-alone acuum was used SMENA head for SE by NTMDT M images. ED , equipped S 152 analysis was conducted with an operating voltage of 20 kV, always in low vacuum. Samples were with a Bruker silicon probe model NCHV working in semi-contact mode. The samples were fixed onto 153 fixed on aluminum sample holders by means of a graphitic adhesive. metallic stubs using a small piece of double-sided scotch tape and studied at RT. 154 AFM characterization was performed using a stand-alone SMENA head by NTMDT, equipped 155 with a Bruker silicon probe model NCHV working in semi-contact mode. The samples were fixed 3. Results 156 onto metallic stubs using a small piece of double-sided scotch tape and studied at RT. 3.1. Sol–Gel Synthesis and Coating Application 157 3. Results To obtain a controlled drug release fabric, 3-glycidoxypropyltriethoxysilane (GPTES) was 158 3.1. Sol–Gel synthesis and coating application employed in a sol–gel synthesis in the presence of an antioxidant/anti-inflammatory molecule, the N-Palmitoyl-(4-nitro-phenyl)-amine (PNPA) [28]. The simultaneous presence of both an epoxy 159 To obtain a controlled drug release fabric, 3-glycidoxypropyltriethoxysilane (GPTES) was 160 group employed and a triethoxysilane in a sol–gel synt functionalities hesis in the presence o makes f an this antspecific ioxidant/ant silica i-infl pr ammat ecursor ory molec able to ule cr , toss-link he N- to 161 Palmitoyl-(4-nitro-phenyl)-amine (PNPA) [28]. The simultaneous presence of both an epoxy group other GPTES molecules, to entrap the antioxidant doping molecule and still to coat the textile surface, 162 and a triethoxysilane functionalities makes this specific silica precursor able to cross-link to other respectively. In this regard, a GPTES-based sol was synthesized in acidic aqueous medium by addition 163 GPTES molecules, to entrap the antioxidant doping molecule and still to coat the textile surface, of slight amount of HCl, as catalyst, and then added to a methanol solution containing the PNPA 164 respectively. In this regard, a GPTES-based sol was synthesized in acidic aqueous medium by molecule. As reported in previous studies [15–21], the sol–gel synthesis leads to the formation of a 165 addition of slight amount of HCl, as catalyst, and then added to a methanol solution containing the hybrid polymeric 3D network through the opening of the epoxy ring of GPTES and interaction of the 166 PNPA molecule. As reported in previous studies [15–21], the sol–gel synthesis leads to the formation triethoxysilane end to form an extended polyethylene oxide network (PEO) [20], in whose holes the 167 of a hybrid polymeric 3D network through the opening of the epoxy ring of GPTES and interaction PNPA is physically and stably entrapped (Scheme 1). 168 of the triethoxysilane end to form an extended polyethylene oxide network (PEO) [20], in whose holes 169 the PNPA is physically and stably entrapped (Scheme 1). 171 Scheme Scheme 1 1. Reaction . Reaction pathways toward the pathways toward the formation formation of of the G-PNPA so the G-PNPA sol, l, as obta as obtained ined in methanol in methanol 172 solution at room temperature in slight acid conditions. solution at room temperature in slight acid conditions. 173 The so obtained G-PNPA functional sol was applied by padding on cotton fabrics and cured 174 thermally with the aim to prepare a nano-hybrid coating for controlled release application (Scheme 175 2). Appl. Sci. 2020, 10, 2287 5 of 13 Appl. The Sci. so 2020obtained , 10, x FOR PG-PNP EER REVIEW A functional sol was applied by padding on cotton fabrics and 5 of cur 13 ed Appl. Sci. 2020, 10, x FOR PEER REVIEW 5 of 13 thermally with the aim to prepare a nano-hybrid coating for controlled release application (Scheme 2). Scheme 2. Schematic representation of the application of the G-PNPA sol on cotton surface and the 177 Scheme 2. Schematic representation of the application of the G-PNPA sol on cotton surface and the 177 Scheme 2. Schematic representation of the application of the G-PNPA sol on cotton surface and the formation of the coating xerogel. 178 formation of the coating xerogel. 178 formation of the coating xerogel. 3.2. Sol NMR Characterization 179 3.2. Sol NMR characterization 179 3.2. Sol NMR characterization A reaction mixture relative to the G-PNPA sol as obtained in methanol for coating application, 180 A reaction mixture relative to the G-PNPA sol as obtained in methanol for coating application, 180 A reaction mixture relative to the G-PNPA sol as obtained in methanol for coating application, has been achieved in situ (1:0.1 = [GPTES]:[PNPA] molar ratio) in methanol-d and characterized by 181 has been achieved in situ (1:0.1=[GPTES]:[PNPA] molar ratio) in methanol-d4 and char 4 acterized by 181 has been 1 achieved in situ (1:0.1=[GPTES]:[PNPA] molar ratio) in methanol-d4 and char 1 acterized by 1 1 182 meansmea of ns of H one- H one- and and two-dimensional two-dimensional NM NMR R spectro spectrsoscopy copy. Fig . u Figur re 1 shows e 1 shows the H N the MR H sp NMR ectra as spectra 1 1 182 means of H one- and two-dimensional NMR spectroscopy. Figure 1 shows the H NMR spectra as 183 recorded at time zero and after 24 h (in methanol-d4 at 298 K, 300 MHz). The comparison of the as recorded at time zero and after 24 h (in methanol-d at 298 K, 300 MHz). The comparison of the 183 recorded at time zero and after 24 h (in methanol-d4 at 298 K, 300 MHz). The comparison of the 184 aliphatic regions of the H NMR spectra of the reaction mixtures recorded at different times clearly aliphatic regions of the H NMR spectra of the reaction mixtures recorded at di erent times clearly 184 aliphatic regions of the H NMR spectra of the reaction mixtures recorded at different times clearly 185 reveal the presence of the protonic pattern expected for the diol/PEO silylated (red squares in Figure reveal the presence of the protonic pattern expected for the diol/PEO silylated (red squares in Figure 1) 185 reveal the presence of the protonic pattern expected for the diol/PEO silylated (red squares in Figure 186 1) derivatives and the starting GPTES (black squares in Figure 1, [20]) as shown in Scheme 1. In derivatives and the starting GPTES (black squares in Figure 1, [20]) as shown in Scheme 1. In particular, 186 187 1) der paivat rticul ive ar, the al s and tih pha e st tic regi arting G ons of PTE the S (b H NM lack s R qspec uaretra in s in Fi Figure gure 1 clear 1, [20]l) y sho as show w: (i) the pr n in Schem esence o e 1. f In the aliphatic regions of the H NMR spectra in Figure 1 clearly show: (i) the presence of the expected 188 the expected protonic pattern for the GPTES open ring derivative, bringing a hydroxyl and an ether 187 particular, the aliphatic regions of the H NMR spectra in Figure 1 clearly show: (i) the presence of protonic pattern for the GPTES open ring derivative, bringing a hydroxyl and an ether group bonded to 189 group bonded to two vicinal carbon Ce and Cf atoms (δ = 0.68, CH2a; 1.71, CH2b; 3.48, CH2c + CH2d + 188 the expected protonic pattern for the GPTES open ring derivative, bringing a hydroxyl and an ether two vicinal carbon C and C atoms ( = 0.68, CH ; 1.71, CH ; 3.48, CH + CH + CH ; 3.88 CH , 190 CH2f; 3.88 CH2e, red squares in lower spectrum) [30] (ii) the proton peaks relative to the starting e f 2a 2b 2c 2d 2f 2e 189 group bonded to two vicinal carbon Ce and Cf atoms (δ = 0.68, CH2a; 1.71, CH2b; 3.48, CH2c + CH2d + 191 GPTES in a decreased concentration (δ = 0.67, CH2a; 1.68, CH2b; 2.61+2.78, CH2f; 3.16, CH2e; 3.32 + 3.76, red squares in lower spectrum) [30] (ii) the proton peaks relative to the starting GPTES in a decreased 190 CH2f; 3.88 CH2e, red squares in lower spectrum) [30] (ii) the proton peaks relative to the starting 192 CH2d; 3.49, CH2c, black squares in upper spectrum); (iii) the presence of the upper-field methylene concentration ( = 0.67, CH ; 1.68, CH ; 2.61+2.78, CH ; 3.16, CH ; 3.32 + 3.76, CH ; 3.49, CH , 2a 2b 2f 2e 2d 2c 191 GPTES in a decreased concentration (δ = 0.67, CH2a; 1.68, CH2b; 2.61+2.78, CH2f; 3.16, CH2e; 3.32 + 3.76, 193 and the methyl proton resonances relative to free ethanol moieties, compared to those relative to the black squares in upper spectrum); (iii) the presence of the upper-field methylene and the methyl proton 192 CH2d; 3.49, CH2c, black squares in upper spectrum); (iii) the presence of the upper-field methylene 194 ethylic groups of GPTES (δ = 3.63, CH2, 1.19, CH3 vs 3.84, CH2, 1.22, CH3; cut signals in both spectra). resonances relative to free ethanol moieties, compared to those relative to the ethylic groups of GPTES 193 and the methyl proton resonances relative to free ethanol moieties, compared to those relative to the 194 ( e = th 3.63, ylic g CH roups , 1.19, of GP CH TES ( vsδ = 3.84, 3.63 CH , CH ,21.22, , 1.19, CH CH3 ; vs cut 3.signals 84, CH2, 1.22 in both , CH spectra). 3; cut signals in both spectra). 2 3 2 3 196 Figure 1. H NMR spectra relative to solutions of the G-PNPA sol, as obtained in methanol-d4 at 298 197 K, 300 MHz, at time zero (upper spectrum) and after 24 h reaction time in the presence of slight 198 amount of HCl (lower spectrum). Figure 1. H 1 NMR spectra relative to solutions of the G-PNPA sol, as obtained in methanol-d at 298 K, 197 Figure 1. H NMR spectra relative to solutions of the G-PNPA sol, as obtained in methanol-d4 at 298 300 MHz, at time zero (upper spectrum) and after 24 h reaction time in the presence of slight amount of 198 K, 300 MHz, at time zero (upper spectrum) and after 24 h reaction time in the presence of slight HCl (lower spectrum). 199 amount of HCl (lower spectrum). Appl. Sci. 2020, 10, 2287 6 of 13 Appl. Sci. 2020, 10, x FOR PEER REVIEW 6 of 13 Unfortunately, the long penta-decanoic protonic chain is buried under other signals, also due 200 Unfortunately, the long penta-decanoic protonic chain is buried under other signals, also due to to the strong molar ratio exceed of GPTES. The aromatic region shows the expected and unchanged 201 the strong molar ratio exceed of GPTES. The aromatic region shows the expected and unchanged pattern of broad signals for para-substituted phenyl ring of the PNPA molecule. 202 pattern of broad signals for para-substituted phenyl ring of the PNPA molecule. The H NMR experiments clearly show that the GPTES epoxy ring opening reaction by a suitable 203 The H NMR experiments clearly show that the GPTES epoxy ring opening reaction by a suitable nucleophilic group of the PNPA molecule is not occurring, as well as the formation of a stable ether 204 nucleophilic group of the PNPA molecule is not occurring, as well as the formation of a stable ether covalent bond. As previously shown [20], the stable encapsulation of the PNPA molecule into the 205 covalent bond. As previously shown [20], the stable encapsulation of the PNPA molecule into the PEO silylated GPTES derivative is most likely due to the formation of weak bonds (i.e., van der Waals 206 PEO silylated GPTES derivative is most likely due to the formation of weak bonds (i.e., van der Waals or electrostatic) between the polymerized GPTES (i.e., ether oxygen and hydroxyl group) and the 207 or electrostatic) between the polymerized GPTES (i.e., ether oxygen and hydroxyl group) and the N- N-Palmitoyl-(4-nitro-phenyl)-amine (i.e., nitrogen, oxygen, long alkyl chain, phenyl group). 208 Palmitoyl-(4-nitro-phenyl)-amine (i.e., nitrogen, oxygen, long alkyl chain, phenyl group). 3.3. ATR FT-IR 209 3.3. ATR FT-IR FT-IR spectra of untreated and treated cotton fabrics were analyzed after the normalization at 1362 210 FT-IR spectra of untreated and treated cotton fabrics were analyzed after the normalization at cm , absorption band relative to the CH bending of cellulose. In Figure 2, FT-IR of CO untreated -1 211 1362 cm , absorption band relative to the CH bending of cellulose. In Figure 2, FT-IR of COL untreated and treated samples with GPTES sol and G-PNPA sol (CO _UT, CO _GPTES and CO _G-PNPA, L L L 212 and treated samples with GPTES sol and G-PNPA sol (COL_UT, COL_GPTES and COL_G-PNPA, respectively) are reported and compared with those relative to CO untreated and treated fabrics 213 respectively) are reported and compared with those relative to COH untreated and treated fabrics with the same solutions (CO _UT, CO _GPTES and CO _G-PNPA, respectively). In particular, in all H H H 214 with the same solutions (COH_UT, COH_GPTES and COH_G-PNPA, respectively). In particular, in all spectra, it is possible to distinguish clearly the characteristic absorption bands relative to cellulose 1 1 215 spectra, it is possible to distinguish clearly the characteristic absorption bands relative to cellulose moieties, such as: the broad bands around to 3331 cm and 2894 cm (stretching mode of OH and CH, ₋1 ₋1 1 1 216 moieties, such as: the broad bands around to 3331 cm and 2894 cm (stretching mode of OH and respectively), and the absorption bands between 1097 cm and 895 cm relative to the asymmetric ₋1 ₋1 217 CH, respectively), and the absorption bands between 1097 cm and 895 cm relative to the in-plane ring stretch and to C–O stretch and asymmetric out-of-phase ring stretch (C –O–C ) [31]. 1 4 218 asymmetric in-plane ring stretch and to C–O stretch and asymmetric out-of-phase ring stretch (C1– In particular, in the inset in Figure 2A,B the presence of a silica coating is evident through the increase 1 1 219 O–C4) [31]. In particular, in the inset in Figure 2A–B the presence of a silica coating is evident through of the bands in the range 1145 cm –895 cm for the CO , assigned to the asymmetric stretching of ₋1 ₋1 1 1 220 the increase of the bands in the range 1145 cm –895 cm for the COL, assigned to the asymmetric the -Si–O–Si, and in the range between 995 cm –760 cm for the CO , due to the Si–O–Si absorption ₋1 ₋1 1 1 221 stretching of the -Si–O–Si, and in the range between 995 cm –760 cm for the COH, due to the Si–O– bending (852 cm ) and stretching (790 cm ). ₋1 ₋1 222 Si absorption bending (852 cm ) and stretching (790 cm ). Figure 2. FT-IR spectra of CO and CO untreated and treated with GPTES sol and G-PNPA sol (A L H 224 Figure 2. FT-IR spectra of COL and COH untreated and treated with GPTES sol and G-PNPA sol (A and B, respectively). (A) FT-IR spectra of CO untreated and treated with GPTES sol and G-PNPA sol; 225 and B, respectively).A) FT-IR spectra of COL untreated and treated with GPTES sol and G-PNPA sol; (B) FT-IR spectra of CO untreated and treated with GPTES sol and G-PNPA sol. 226 B) FT-IR spectra of COH untreated and treated with GPTES sol and G-PNPA sol. With the aim of investigating the chemical structure and interactions between silica precursor 227 With the aim of investigating the chemical structure and interactions between silica precursor and antioxidant molecule without the interference of the intense absorption bands of cotton fabrics, 228 and antioxidant molecule without the interference of the intense absorption bands of cotton fabrics, the FT-IR spectra of each sol was carried out on the pure xerogel. The latter was obtained by depositing 229 the FT-IR spectra of each sol was carried out on the pure xerogel. The latter was obtained by 230 depositing a few drops of each solution onto optical glass slides further subjected to a thermal 231 treatment (100 °C) to remove the solvent [26]. Indeed, by analyzing the FT-IR spectra of PNPA, it was Appl. Sci. 2020, 10, x FOR PEER REVIEW 7 of 13 232 possible to identify the characteristic peaks in order to establish its interaction with the GPTES sol. 233 Spectra of the GPTES sol (Figure 3, green line) clearly shows the formation of the inorganic network Appl. Sci. 2020, 10, 2287 7 of 13 ₋1 234 due to the absorption bands relative to: asymmetric (1093–1010 cm ) and symmetric stretching of Si– ₋1 ₋1 235 O–Si (756 cm ) and its bending mode (850 cm ) [17,18,20]. Furthermore, the absorption bands at a few drops of each ₋1 solution ₋1 onto optical glass ₋1 slides further subjected to a thermal treatment (100 C) 236 3072–3000 cm , 1255 cm and 906–850 cm were assigned to asymmetric and symmetric C–H stretch, to remove the solvent [26]. Indeed, by analyzing the FT-IR spectra of PNPA, it was possible to identify 237 ring breathing, as well as the asymmetric and symmetric ring deformation, respectively [17,18], the characteristic peaks in order to establish its interaction with the GPTES sol. Spectra of the GPTES 238 indicating that some unopened epoxy ring remain in GPTES sol. sol (Figure 3, green line) clearly shows the formation of the inorganic network due to the absorption 239 These peaks relative to the GPTES sol are also evidenced in the sol containing PNPA (Figure 3, 1 1 bands relative to: asymmetric (1093–1010 cm ) and symmetric stretching of Si–O–Si (756 cm ) and its 240 black line), in which the main characteristic absorption bands of the antioxidant molecules are 1 1 1 bending mode (850 cm ) [17,18,20]. Furthermore, the absorption bands at 3072–3000 cm , 1255 cm 241 present. As shown in Figure 2 (red line), PNPA is featured by the asymmetric and symmetric CH2 ₋1 and 906–850 cm were assigned to asymmetric and symmetric C–H stretch, ring breathing, as well as 242 stretching mode of alkyl chain (2916 and 2849 cm , respectively) with relative bending (1470–1458 the asymmetric ₋1 and symmetric ring deformation, respectively [17,18], indicating₋1 that some unopened 243 cm ), the C=O and C–N stretching of the secondary amide (1737 and 3075 cm , respectively) and the ₋1 epoxy ring remain in GPTES sol. 244 C–N stretching mode (1596 cm ) [32]. Figure 3. FT-IR spectra of PNPA, GPTES sol and G-PNPA sol. 246 Figure 3. FT-IR spectra of PNPA, GPTES sol and G-PNPA sol. These peaks relative to the GPTES sol are also evidenced in the sol containing PNPA (Figure 3, 247 3.4. Morphological characterizations black line), in which the main characteristic absorption bands of the antioxidant molecules are present. As shown in Figure 2 (red line), PNPA is featured by the asymmetric and symmetric CH stretching 248 All untreated and treated cotton samples were investigated by SEM and AFM microscopy, in 1 1 mode of alkyl chain (2916 and 2849 cm , respectively) with relative bending (1470–1458 cm ), 249 order to characterize the morphology of the coated textile fabric and to underline structural the C=O and C–N stretching of the secondary amide (1737 and 3075 cm , respectively) and the C–N 250 differences before and after the coating application. stretching mode (1596 cm ) [32]. 251 SEM analysis shows that the two analyzed tissues have two different weaves: COH_UT samples 252 have a larger weave than COL_UT ones, and the fibers appear less ordered compared with COL_UT 3.4. Morphological Characterizations 253 ones and more threadbare (compare Figure 4a and 4b). Both samples do not show modifications after All untreated and treated cotton samples were investigated by SEM and AFM microscopy, in order to characterize the morphology of the coated textile fabric and to underline structural di erences before and after the coating application. Appl. Sci. 2020, 10, 2287 8 of 13 SEM analysis shows that the two analyzed tissues have two di erent weaves: CO _UT samples have a larger weave than CO _UT ones, and the fibers appear less ordered compared with CO _UT ones L L and more threadbare (compare Figure 4a,b). Both samples do not show modifications after treatment Appl. Sci. 2020, 10, x FOR PEER REVIEW 8 of 13 Appl. Sci. 2020, 10, x FOR PEER REVIEW 8 of 13 and the morphology appears unchanged also at higher magnification (Figure 5). This demonstrates 254 that, trea after tment a treatment, nd the morphol no changes ogy at appears uncha micrometer scale nged a occur lso .at higher magnification (Figure 5). This 254 treatment and the morphology appears unchanged also at higher magnification (Figure 5). This 255 demonstrates that, after treatment, no changes at micrometer scale occur. 255 demonstrates that, after treatment, no changes at micrometer scale occur. 257 257 Figure 4. Figure 4. SE SEM analysis M analysis of of invest investigated igated samples: samples: CO CO H H_UT ( _UT ( aa), CO ), CO LL_UT ( _UT ( b b),), CO CO H H_GPTES ( _GPTES ( cc ), ), Figure 4. SEM analysis of investigated samples: CO _UT (a), CO _UT (b), CO _GPTES (c), H L H 258 258 CO CO LL _GPTES ( _GPTES ( d d ), CO ), CO H H _G-PNPA ( _G-PNPA ( ee ), CO ), CO LL _G-PNPA ( _G-PNPA ( ff ). ). CO _GPTES (d), CO _G-PNPA (e), CO _G-PNPA (f). L H L 260 260 Figure 5. Figure 5. SEM SEM analysis of analysis of inv inveestigated stigated samples at samples at higher magnification: higher magnification: CO CO H H_UT _UT ( ( aa), CO ), CO LL_UT ( _UT ( b b ), ), Figure 5. SEM analysis of investigated samples at higher magnification: CO _UT (a), CO _UT (b), H L 261 261 CO CO H H _GPTES ( _GPTES ( cc ), CO ), CO LL _GPTES ( _GPTES ( d d ), CO ), CO H H _G-PNPA ( _G-PNPA ( ee ),), CO CO LL _G- _G- P P NPA ( NPA ( ff ). ). CO _GPTES (c), CO _GPTES (d), CO _G-PNPA (e), CO _G-PNPA (f). H L H L 262 262 EDS EDS an analy alyssis is shows shows S Sii pe peak ak only only in in s saamples t mples trreeaatteedd wit withh GPTE GPTESS (CO (CO H H_G _GPT PTEESS, C , CO O LL _G _G PTE PTE SS ) ) 263 263 aa n n d su d su bs bs eq eq u u ee ntl ntl y y wi wi th th P P N N P P A A ( ( C C O O H H _G _G -P -P NPA NPA , C , C O O LL __ G G -PN -PN P P A) (Fi A) (Fi g g u u rr e e 66 , only two t , only two t rr ea ea ted sa ted sa mples mples aa rr e e 264 264 reported reported for for briefne briefne ss, bec ss, bec aa use the use the othe othe r ones exh r ones exh ii bi bi tt ed ed a a sim sim ii lar lar spectrum). Th spectrum). Th e other e other peak peak s s refer refer to to Appl. Sci. 2020, 10, 2287 9 of 13 EDS analysis shows Si peak only in samples treated with GPTES (CO _GPTES, CO _GPTES) Appl. Sci. 2020, 10, x FOR PEER REVIEW 9 of 13 H L and subsequently with PNPA (CO _G-PNPA, CO _G-PNPA) (Figure 6, only two treated samples are H L 265 carbon, present in the analyzed tissues but also in graphite adhesive used for SEM analysis, oxygen, reported for briefness, because the other ones exhibited a similar spectrum). The other peaks refer to 266 present also in vapor-low vacuum atmosphere, and aluminum, derived from the SEM stub. carbon, present in the analyzed tissues but also in graphite adhesive used for SEM analysis, oxygen, 267 The mapping presented in Figure 6 (inset c* and d*) shows that distribution of Si element present also in vapor-low vacuum atmosphere, and aluminum, derived from the SEM stub. 268 (present in GPTES) is very uniform and no phase separation occurs. Figure 6. EDS analysis of investigated samples: CO _UT (a), CO _UT (b), CO _G-PNPA (c), 270 Figure 6. EDS analysis of investigated samples: COH_UTH (a), COL_UT (b L), COH_G-PNPA ( H c), COL_G- CO _G-PNPA (d), and mapping of CO _G-PNPA (inset c*) and CO _G-PNPA (inset d*). 271 PNPA L (d), and mapping of COH_G-PNPA ( H inset c*) and COL_G-PNPA (inset L d*). The mapping presented in Figure 6 (inset c* and d*) shows that distribution of Si element 272 3.5. AFM characterizations (present in GPTES) is very uniform and no phase separation occurs. 273 Figure 7 shows that all the studied sampled are characterized by the typical filamentary 274 structure 3.5. AFM of t Characterizations he tissue fibers on the nanoscale. Figure 7 shows that all the studied sampled are characterized by the typical filamentary structure of the tissue fibers on the nanoscale. Thanks to the high resolution achieved by the AFM technique, it is possible to notice that both the two sample pairs CO _GPTES (Figure 7c), CO _GPTES (Figure 7d) and CO _G-PNPA (Figure 7e), L H L CO _G-PNPA (Figure 7f) are rougher than the untreated tissues CO _UT (Figure 7a), CO _UT H L H (Figure 7b), indicating that the GPTES and PNPA intimately and homogeneously wrap the fibers. This result is in good agreement with the EDS Si mapping. In the lower right corner of Figure 7f, it is possible to observe the presence of a lack in the coating; the study of the line profiles in that area allows us to evaluate the thickness of the coating that ranges between 2.5 and 4 nm. 275 Appl. Sci. 2020, 10, x FOR PEER REVIEW 9 of 13 265 carbon, present in the analyzed tissues but also in graphite adhesive used for SEM analysis, oxygen, 266 present also in vapor-low vacuum atmosphere, and aluminum, derived from the SEM stub. 267 The mapping presented in Figure 6 (inset c* and d*) shows that distribution of Si element 268 (present in GPTES) is very uniform and no phase separation occurs. 270 Figure 6. EDS analysis of investigated samples: COH_UT (a), COL_UT (b), COH_G-PNPA (c), COL_G- 271 PNPA (d), and mapping of COH_G-PNPA (inset c*) and COL_G-PNPA (inset d*). 272 3.5. AFM characterizations Appl. Sci. 2020, 10, 2287 10 of 13 273 Figure 7 shows that all the studied sampled are characterized by the typical filamentary 274 structure of the tissue fibers on the nanoscale. Appl. Sci. 2020, 10, x FOR PEER REVIEW 10 of 13 276 Figure 7. AFM micrograph of COL_UT (a), COH_UT (b), COL_GPTES (c), COH_GPTES (d), COL_G- 277 PNPA (e), and COH_G-PNPA (f). 278 Thanks to the high resolution achieved by the AFM technique, it is possible to notice that both 279 the two sample pairs COL_GPTES (Figure 7c), COH_GPTES (Figure 7d) and COL_G-PNPA (Figure 280 7e), COH_G-PNPA (Figure 7f) are rougher than the untreated tissues COL_UT (Figure 7a), COH_UT 281 (Figure 7b), indicating that the GPTES and PNPA intimately and homogeneously wrap the fibers. 282 This result is in good agreement with the EDS Si mapping. In the lower right corner of Figure 7f, it is Figure 7. AFM micrograph of CO _UT (a), CO _UT (b), CO _GPTES (c), CO _GPTES (d), L H L H 283 possible to observe the presence of a lack in the coating; the study of the line profiles in that area CO _G-PNPA (e), and CO _G-PNPA (f). L H 284 allows us to evaluate the thickness of the coating that ranges between 2.5 and 4 nm. 3.6. PNPA in Vitro Di usion Studies 285 3.6. PNPA in vitro diffusion studies In vitro di usion studies on the developed cotton-based textiles were carried out with the aim of 286 In vitro diffusion studies on the developed cotton-based textiles were carried out with the aim evaluating their ability to release in a controlled manner the synthesized PEA derivative compared to a 287 of evaluating their ability to release in a controlled manner the synthesized PEA derivative compared standard solution of the molecule (Scheme 3). 288 to a standard solution of the molecule (Scheme 3). Scheme 3. Schematic representation on the PNPA controlled release from the functional sol–gel coated 290 Scheme 3. Schematic representation on the PNPA controlled release from the functional sol–gel cotton by stimuli e ect. 291 coated cotton by stimuli effect. In the performed experiments, Strat-M membranes were used as a synthetic alternative, which 292 In the performed experiments, Strat-M membranes were used as a synthetic alternative, which is predictive of the di usion process occurring through human skin. The studies involved two 293 is predictive of the diffusion process occurring through human skin. The studies involved two di erent textiles, such as CO _G-PNPA and CO _G-PNPA, prepared employing the obtained G-PNPA L H 294 different textiles, such as COL_G-PNPA and COH_G-PNPA, prepared employing the obtained G- functional sol. The obtained results are expressed as cumulative di used amount (%) and the di usion 295 PNPA functional sol. The obtained results are expressed as cumulative diffused amount (%) and the profiles for the tested items are reported in Figure 8. 296 diffusion profiles for the tested items are reported in Figure 8. 298 Figure 8. In vitro diffusion profiles. 299 The two G-PNPA-coated cotton textiles, COL_G-PNPA and COH_G-PNPA, show similar results 300 in the performed in vitro diffusion studies. In the case of the COL_G-PNPA sample, indeed, the 301 amount of released PNPA is equal to 5% within the first hour reaching the 48% and 66% in 6 and 24 302 h, respectively, while the COH_G-PNPA sample exhibits a value of 7% after the first hour achieving Appl. Sci. 2020, 10, x FOR PEER REVIEW 10 of 13 276 Figure 7. AFM micrograph of COL_UT (a), COH_UT (b), COL_GPTES (c), COH_GPTES (d), COL_G- 277 PNPA (e), and COH_G-PNPA (f). 278 Thanks to the high resolution achieved by the AFM technique, it is possible to notice that both 279 the two sample pairs COL_GPTES (Figure 7c), COH_GPTES (Figure 7d) and COL_G-PNPA (Figure 280 7e), COH_G-PNPA (Figure 7f) are rougher than the untreated tissues COL_UT (Figure 7a), COH_UT 281 (Figure 7b), indicating that the GPTES and PNPA intimately and homogeneously wrap the fibers. 282 This result is in good agreement with the EDS Si mapping. In the lower right corner of Figure 7f, it is 283 possible to observe the presence of a lack in the coating; the study of the line profiles in that area 284 allows us to evaluate the thickness of the coating that ranges between 2.5 and 4 nm. 285 3.6. PNPA in vitro diffusion studies 286 In vitro diffusion studies on the developed cotton-based textiles were carried out with the aim 287 of evaluating their ability to release in a controlled manner the synthesized PEA derivative compared 288 to a standard solution of the molecule (Scheme 3). 290 Scheme 3. Schematic representation on the PNPA controlled release from the functional sol–gel 291 coated cotton by stimuli effect. 292 In the performed experiments, Strat-M membranes were used as a synthetic alternative, which 293 is predictive of the diffusion process occurring through human skin. The studies involved two 294 different textiles, such as COL_G-PNPA and COH_G-PNPA, prepared employing the obtained G- 295 PNPA functional sol. The obtained results are expressed as cumulative diffused amount (%) and the Appl. Sci. 2020, 10, 2287 11 of 13 296 diffusion profiles for the tested items are reported in Figure 8. Figure 8. In vitro di usion profiles. 298 Figure 8. In vitro diffusion profiles. The two G-PNPA-coated cotton textiles, CO _G-PNPA and CO _G-PNPA, show similar results in L H 299 The two G-PNPA-coated cotton textiles, COL_G-PNPA and COH_G-PNPA, show similar results the performed in vitro di usion studies. In the case of the CO _G-PNPA sample, indeed, the amount of 300 in the performed in vitro diffusion studies. In the case of the COL_G-PNPA sample, indeed, the released PNPA is equal to 5% within the first hour reaching the 48% and 66% in 6 and 24 h, respectively, 301 amount of released PNPA is equal to 5% within the first hour reaching the 48% and 66% in 6 and 24 while the CO _G-PNPA sample exhibits a value of 7% after the first hour achieving the 53% and 73% 302 h, respectively, while the COH_G-PNPA sample exhibits a value of 7% after the first hour achieving at the time points of 6 and 24 h. On the other hand, the 14% of PNPA is released after the first hour from the control solution reaching the 69% and 89% at 6 and 24 h. The experimental data confirm the ability of both the developed textiles to release in a controlled way the synthesized PEA derivative. These results could be related to the rate-limiting steps in drug release reported in the literature [33,34]: the drug di usion within the polymer matrix and the rate of polymer swelling. Depending on the presence of sweat, simulated with the bu er solution in contact with the PNPA-treated fabric, the weak interactions between the treated fabric and the antioxidant molecule slowly disappear until the drug is completely released. The presence of the sol–gel matrix increases the bonding interactions between the network and the drug, slowing down its release. 4. Conclusions The N-Palmitoyl-(4-nitro-phenyl)-amine, PNPA, a PEA derivative that already showed good anti-inflammatory and antioxidant properties, was firmly entrapped in a sol–gel-based matrix obtained by polymerization reaction of the epoxy-alkoxysilane GPTES, as cross-linker compound. NMR studies run on the sol evidenced that the GPTES epoxy-ring opening and the subsequent polymerization give rise to a polyethylene oxide 3D network grafted on textile with the PNPA immobilized into it. After the textile drying and curing the xerogel was morphologically studied on the treated cotton samples by SEM and AFM microscopy, revealing that no changes in the fiber morphology occurred at the micrometer scale, and that GPTES and PNPA intimately and homogeneously wrap the fibers. Furthermore, SEM mapping revealed a uniform distribution of the silica-based coating on the cotton fibers. In vitro di usion studies were realized on the developed functionalized cotton-based textiles in order to check their ability to release the PEA derivative in a controlled manner in comparison to a standard molecule solution. As a matter of fact, this functional textile has been shown to be a suitable system for PNPA release, thanks to the chemical binding weakening of PNPA with the sol–gel polymer matrix by mean of medium e ect, thus opening the way to the design of similar functional hybrid coatings for biomedical application. Although parameters of sol particles (e.g., hydrodynamic radius and electrokinetic potential) as well as the porosity of systems were not investigated, the obtained results confirmed the potential of the nanoengineered procedure as a versatile method for preparing stable and tunable drug-releasing materials. The combination of the functionality and transparency provided by the hybrid coating with its easy processability could represent an innovative route to fabricate biomaterials for healthcare. Future work will focus on the comparison of silica sols characteristics with release properties of this delivery system. Appl. Sci. 2020, 10, 2287 12 of 13 Author Contributions: Conceptualization was done by M.S.S., G.R. and M.R.P. Investigation was performed by F.P., O.I.P., C.S., M.G.B., V.T., G.R., C.T., C.M., E.P., M.S.S., D.I., M.R.P. and D.D. Project administration was directed by M.S.S., G.R. and M.R.P. Resources were provided by F.P., O.I.P., C.S., M.G.B., V.T., G.R., C.T., C.M., E.P., M.S.S., D.I., M.R.P. and D.D. Supervision was taken care of by M.S.S., G.R. and M.R.P. Validation was carried out by F.P. and O.I.P. Visualization and original draft writing was done by M.S.S., G.R. and M.R.P. All authors have read and agreed to the published version of the manuscript. Funding: This research received no external funding. Acknowledgments: MURST: CNR and MIUR are gratefully acknowledged for financial support. Conflicts of Interest: The authors declare no conflict of interest. References 1. Langer, R. Drug delivery and targeting. Nature 1998, 392, 5–10. 2. Brouwers, J.R.B.J. 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This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Applied Sciences Multidisciplinary Digital Publishing Institute

Sol–Gel Treatment of Textiles for the Entrapping of an Antioxidant/Anti-Inflammatory Molecule: Functional Coating Morphological Characterization and Drug Release Evaluation

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applied sciences Article Sol–Gel Treatment of Textiles for the Entrapping of an Antioxidant/Anti-Inflammatory Molecule: Functional Coating Morphological Characterization and Drug Release Evaluation 1 2 3 1 Francesco Puoci , Carmela Saturnino , Valentina Trovato , Domenico Iacopetta , 4 5 2 6 Elpida Piperopoulos , Claudia Triolo , Maria Grazia Bonomo , Dario Drommi , 1 4 1 , 3 , Ortensia Ilaria Parisi , Candida Milone , Maria Stefania Sinicropi * , Giuseppe Rosace * 7 , and Maria Rosaria Plutino * Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Via Pietro Bucci, 87036 Arcavacata di Rende (CS), Italy; francesco.puoci@unical.it (F.P.); domenico.iacopetta@unical.it (D.I.); ortensiailaria.parisi@unical.it (O.I.P.) Department of Science, University of Basilicata, Viale dell’Ateneo Lucano 10, 85100 Potenza, Italy; carmela.saturnino@unibas.it (C.S.); mariagrazia.bonomo@unibas.it (M.G.B.) Department of Engineering and Applied Sciences, University of Bergamo, Viale Marconi 5, 24044 Dalmine (BG), Italy; valentina.trovato@unibg.it Department of Engineering, University of Messina, Contrada di Dio, S.Agata, 98166 Messina (ME), Italy; epiperopoulos@unime.it (E.P.); candida.milone@unime.it (C.M.) Department of Mathematics and Computer science, Physical and Earth Sciences, University of Messina, Viale F. Stagno d’Alcontres 31, Vill. S. Agata, 98166 Messina (ME), Italy; claudia.triolo@unime.it Department of ChiBioFarAm, University of Messina, Viale F. Stagno d’Alcontres 31, Vill. S. Agata, 98166 Messina (ME), Italy; ddrommi@unime.it Institute for the Study of Nanostructured Materials, ISMN—CNR, Palermo, c/o Department of ChiBioFarAm, University of Messina, Viale F. Stagno d’Alcontres 31, Vill. S. Agata, 98166 Messina (ME), Italy * Correspondence: s.sinicropi@unical.it (M.S.S.); giuseppe.rosace@unibg.it (G.R.); mariarosaria.plutino@cnr.it (M.R.P.); Tel.: +39-0984-493200 (M.S.S.); +39-035-2052021 (G.R.); +39-090-6765713 (M.R.P.) Received: 13 February 2020; Accepted: 20 March 2020; Published: 27 March 2020 Abstract: The growing interest towards textile-based drug delivery systems is due to their potential innovative medical and well-being applications. In recent years, the technique of encapsulation or inclusion of the medicine/active principle into a polymer functional matrix has been employed in order to obtain textile materials with controlled drug release. In this study, a sol–gel-based coating was developed and used as an entrapping polymeric cross-linked network for a N-Palmitoyl-ethanolamine (PEA) derivative, 2-methyl-pentadecanoic acid (4-nitro-phenyl)-amide or N-Palmitoyl-(4-nitro-phenyl)-amine (PNPA), whose anti-inflammatory and antioxidant properties have already been shown. A wide series of chemical-physical methods have been used to characterize the silica-based functional sol and to ascertain the ecient and temporary deposit of PNPA on the sol–gel coated cotton fabrics. The medicine release system achieved was shown to ensure biocompatibility, PNPA reservoir and its subsequent releasing under the action of cutaneous stimuli, thus providing useful insights in the design of medical textiles. Keywords: sol–gel coating; medical textiles; antioxidant; anti-inflammatory; PEA derivative; drug release 1. Introduction The research field dealing with the development of controlled drug delivery systems has been of relevant scientific interest since the 1970s and has grown and diversified rapidly in recent years, in Appl. Sci. 2020, 10, 2287; doi:10.3390/app10072287 www.mdpi.com/journal/applsci Appl. Sci. 2020, 10, 2287 2 of 13 particular thanks to the benefits it brings to healthcare; furthermore, it covers a large market segment [1]. In general, the e ectiveness of drug therapy is the main objective of controlled release systems [1,2], with a corresponding (i) reduction of the number of drug administrations; (ii) improvement in therapeutic activity [3,4]; (iii) consequent reduction of the intensity of side e ects; and (iv) elimination of specialized drug administration [5]. This pharmaceutical technology, especially in recent years, has seen application in other fields ranging from cosmetics [6] to agriculture [7], including textiles [8,9], as an interesting and innovative application. Indeed, textile fabrics, thanks to their biocompatibility, breathing structure and absorptive capacity, are of great interest as a medium (for ex vivo applications) for controlled release of drugs, active principles or aroma substances of particular comfortability [10]. Several examples are nowadays in common use, such as the well-known transdermal patches or textile costumes, generally characterized by di erent layers in which the release of a specific drug substance, deposited on the textile surface, is activated by stimuli such as temperature, humidity, enzyme, perspiration types or friction [11]. In general, in controlled release systems, biocompatibility and controllability are important features; furthermore, in terms of biocompatibility, the carcinogenicity, toxicity, teratogenicity and mutagenicity are important elements to be controlled [10]. The use of textile fabrics for the realization of controlled release systems presents several advantages but on the other hand, some disadvantages with respect to the oral administration of substances. Indeed, this administration represents an attractive and easier therapy for the patient due to its ecacy since the drug avoids both the digestive apparatus and the hepatic metabolism that reduce the concentration of the drug. Furthermore, it requires lower dosages due to the higher di usion through tissues, which correspond to lower social costs of therapies [11]. On the other hand, the disadvantages are related to the di usion rate of the drug as function of its molecular structure and body surface administration [11]. Di erent methods have been employed in order to develop better textile-based delivery systems (i.e., bandages, patches), with good controllability, biocompatibility and active species entrapment/release by use of host-guest molecules (cyclodextrins [12], aza-crown ethers, fullerenes) or doping functional molecules (ion-exchange; drug-loaded hollow; nanoparticles; bioactive) [10]. Several C–C polymer heteroatom-containing (i.e., N, P, Si) backbones for controlled release applications have been tested and considered in order to improve the drug therapy e ectiveness [5]. All the developed release polymeric systems have been shown to act through mechanisms of temporal controlled release, such as drug-delayed dissolution, di usion-controlled, and drug solution flow control after interaction with environmental water or by reacting to specific skin stimuli. The sol–gel method has been shown to be a useful method in the preparation of functional nanostructured coatings for textiles, thus combining the entrapment/encapsulation of bioactive compounds, biomolecules and their controlled release [13]. In our previous studies, we have already shown that nano-hybrid sol–gel-based coatings feature abrasion resistance, tensile strength and elongation properties of the treated fabrics [13,14]. These peculiar characteristics may be combined with a proper doping molecule, such as a dye [15–21], an antimicrobial [22], a hydrophobic [23–25] or a flame-resistant molecule [26,27], with the aim of improving the textile surface properties and making a functional nano-hybrid coating. With the aim of developing a functional sol–gel-based coating suitable for medical application, we thought worthwhile to make a silica sol containing the 3-glycidoxypropyltriethoxysilane (GPTES, hereafter “G”), as silica cross-linker precursor, and a PEA derivative, the N-Palmitoyl-(4-nitro-phenyl)-amine (hereafter PNPA), whose anti-inflammatory and antioxidant properties have already been tested and compared with other analogue molecules [28]. The sol was successfully applied on cotton surfaces and, after drying and curing, a stable and uniform PNPA-containing silica-based coating was obtained, as confirmed by morphological studies (SEM and AFM microscopy). As already shown in previous studies for halochromic dyestu [20], the PEA derivative results firmly encapsulated into the 3D hybrid silica layer in absence of external stimuli (i.e., variable pH conditions), thanks to non-covalent and weak interactions (i.e., hydrogen bonds Appl. Sci. 2020, 10, 2287 3 of 13 and van der Waals interactions) acting between the non-polar active molecule and the alkoxysilane hosting network. Finally, the functionally coated cotton samples were employed for in vitro di usion studies with the aim of testing their ability to release the synthesized PEA derivative in a controlled manner compared to a standard solution of the molecule. This e ectively prepared functional hybrid system, based on the non-covalently immobilized PNPA, showed good results so that it can be considered a suitable sca old for fabrics in drug release applications, thus providing useful insights in the design and the development of medical textiles. 2. Materials and Methods N-Palmitoyl-(4-nitro-phenyl)-amine (PNPA) was synthetized according to a synthetic strategy described in previous researches [28]. 3-glycidyloxypropyltriethoxysilane (GPTES) and methanol were purchased from Wacker and Aldrich, respectively, and used without further purification. Two cotton scoured and bleached 100% plain-weave textile fabrics (coded CO and CO ) kindly supplied by L H Albini S.p.A. (Albino, Italy) and Mascioni S.p.A. (Cuvio, Italy), respectively, were used for this research. 2 2 The fabrics showed di erent mass per unit area (CO = 119 g/m and CO = 331 g/m , respectively). L H Cotton fabrics were washed before treatment at pH 7 and at 40 C for 20 min in a non-ionic detergent, rinsed several times with de-ionized water and then dried. The cleaned samples were conditioned at 20 ( 1) C and under standard atmospheric pressure at 65 ( 2)% relative humidity for at least 24 h prior to all experiments. PNPA (25 mg) was dissolved in 40 mL of methanol through ultrasonication and left under continuous stirring. Then 2 mL of a 1 M aqueous sol–gel solution of GPTES were added drop by drop to the clear methanol solution of antioxidant molecule, thus resulting in a final GPTES sol concentration of 0.05 M (1:0.034 molar ratio with respect to PNPA). The obtained solution (G-PNPA sol) was ultrasonicated and left at room temperature under stirring for at least 90 min. The same reaction was also carried out in absence of the antioxidant molecule in order to obtain a reference GPTES sol sample. Both solutions were applied separately onto cotton textile (10 cm  10 cm) through a two-roll laboratory padder (Werner Mathis, Zurich, Switzerland) at a nip pressure of 2 bar, then dried (80 C for 5 min) and cured (100 C for 1 min) in an electric laboratory oven. PNPA, G-PNPA and G sols were fully investigated through FT-IR spectroscopy and Nuclear magnetic resonance (NMR). Untreated and treated textiles were characterized by FT-IR spectroscopy, Scanning Electron Microscopy (SEM) coupled to energy dispersive X-ray (EDS) and Atomic Force Microscopy (AFM). The PNPA controlled release from the two prepared textiles, CO _G-PNPA and CO _G-PNPA, L H was investigated by performing in vitro di usion studies using Franz di usion cells and according to the experimental protocol reported in a previous work [29]. For this purpose, Strat-M membranes (25 mm discs, Cat. No. SKBM02560, Merck Millipore, Darmstadt, Germany) were positioned between the donor and the receptor compartments of each Franz cell and the experiments were carried out at 37  0.5 C. The two tested items, CO _G-PNPA and CO _G-PNPA, were placed on L H the Strat-M membrane with the GPTES layer facing towards the acceptor chamber. Then, the Franz cell compartments were fixed together and filled with 0.5 and 5.5 mL of phosphate bu er at pH 7.4 (10 M), respectively. The content of the receptor chamber was withdrawn at di erent times, such as 1, 2, 4, 6 and 24 h, for UV-Vis analysis and replaced with phosphate bu er. The same experimental conditions were applied to a control sample consisting of a standard PNPA solution. The in vitro di usion studies were carried out in triplicate and the obtained results were expressed as di used amount (%). FT-IR spectra were performed by a Thermo Avatar 370 equipped with an attenuated total reflection (ATR) accessory and using a diamond crystal as internal reflectance element. Spectra were acquired 1 1 with 32 scans and in the range from 4000 to 550 cm with a resolution of 4 cm . Appl. Sci. 2020, 10, 2287 4 of 13 One- and two-dimensional NMR experiment were recorded in methanol-d at 298.2 (0.1) K on Bruker ARX-300, equipped with a 5 mm gradient probe and operating at 300.1 MHz for 1H nucleus. All chemical shifts are shown in parts per million (/ppm), downfield to tetramethylsilane (Me Si) as an internal standard ( = 0.0 ppm), or referenced to the residual protiated solvent 1 1 signal such as in methanol-d ( H NMR: 3.30 ppm). H NMR signals were assigned by means of two-dimensional Appl. Sci. 2020, 10, x FO homonuclear R PEER REVIEWNMR gradient experiments (gCOSY, gNOESY), acquir 4 of ed 13 using standard Bruker pulse sequences. 146 an internal standard (δ = 0.0 ppm), or referenced to the residual protiated solvent signal such as in SEM morphology and SEM-EDS of the investigated samples were obtained using a FEI Quanta 1 1 147 methanol-d4 ( H NMR: 3.30 ppm). H NMR signals were assigned by means of two-dimensional FEG 450 microscope. An operating voltage of 5 kV in low vacuum was used for SEM images. EDS 148 homonuclear NMR gradient experiments (gCOSY, gNOESY), acquired using standard Bruker pulse analysis was conducted with an operating voltage of 20 kV, always in low vacuum. Samples were 149 sequences. fixed on aluminum sample holders by means of a graphitic adhesive. 150 SEM morphology and SEM-EDS of the investigated samples were obtained using a FEI Quanta 151 AFM FEG 450 mic characterization roscope. An was operating performed voltage using of 5 a kV in low v stand-alone acuum was used SMENA head for SE by NTMDT M images. ED , equipped S 152 analysis was conducted with an operating voltage of 20 kV, always in low vacuum. Samples were with a Bruker silicon probe model NCHV working in semi-contact mode. The samples were fixed onto 153 fixed on aluminum sample holders by means of a graphitic adhesive. metallic stubs using a small piece of double-sided scotch tape and studied at RT. 154 AFM characterization was performed using a stand-alone SMENA head by NTMDT, equipped 155 with a Bruker silicon probe model NCHV working in semi-contact mode. The samples were fixed 3. Results 156 onto metallic stubs using a small piece of double-sided scotch tape and studied at RT. 3.1. Sol–Gel Synthesis and Coating Application 157 3. Results To obtain a controlled drug release fabric, 3-glycidoxypropyltriethoxysilane (GPTES) was 158 3.1. Sol–Gel synthesis and coating application employed in a sol–gel synthesis in the presence of an antioxidant/anti-inflammatory molecule, the N-Palmitoyl-(4-nitro-phenyl)-amine (PNPA) [28]. The simultaneous presence of both an epoxy 159 To obtain a controlled drug release fabric, 3-glycidoxypropyltriethoxysilane (GPTES) was 160 group employed and a triethoxysilane in a sol–gel synt functionalities hesis in the presence o makes f an this antspecific ioxidant/ant silica i-infl pr ammat ecursor ory molec able to ule cr , toss-link he N- to 161 Palmitoyl-(4-nitro-phenyl)-amine (PNPA) [28]. The simultaneous presence of both an epoxy group other GPTES molecules, to entrap the antioxidant doping molecule and still to coat the textile surface, 162 and a triethoxysilane functionalities makes this specific silica precursor able to cross-link to other respectively. In this regard, a GPTES-based sol was synthesized in acidic aqueous medium by addition 163 GPTES molecules, to entrap the antioxidant doping molecule and still to coat the textile surface, of slight amount of HCl, as catalyst, and then added to a methanol solution containing the PNPA 164 respectively. In this regard, a GPTES-based sol was synthesized in acidic aqueous medium by molecule. As reported in previous studies [15–21], the sol–gel synthesis leads to the formation of a 165 addition of slight amount of HCl, as catalyst, and then added to a methanol solution containing the hybrid polymeric 3D network through the opening of the epoxy ring of GPTES and interaction of the 166 PNPA molecule. As reported in previous studies [15–21], the sol–gel synthesis leads to the formation triethoxysilane end to form an extended polyethylene oxide network (PEO) [20], in whose holes the 167 of a hybrid polymeric 3D network through the opening of the epoxy ring of GPTES and interaction PNPA is physically and stably entrapped (Scheme 1). 168 of the triethoxysilane end to form an extended polyethylene oxide network (PEO) [20], in whose holes 169 the PNPA is physically and stably entrapped (Scheme 1). 171 Scheme Scheme 1 1. Reaction . Reaction pathways toward the pathways toward the formation formation of of the G-PNPA so the G-PNPA sol, l, as obta as obtained ined in methanol in methanol 172 solution at room temperature in slight acid conditions. solution at room temperature in slight acid conditions. 173 The so obtained G-PNPA functional sol was applied by padding on cotton fabrics and cured 174 thermally with the aim to prepare a nano-hybrid coating for controlled release application (Scheme 175 2). Appl. Sci. 2020, 10, 2287 5 of 13 Appl. The Sci. so 2020obtained , 10, x FOR PG-PNP EER REVIEW A functional sol was applied by padding on cotton fabrics and 5 of cur 13 ed Appl. Sci. 2020, 10, x FOR PEER REVIEW 5 of 13 thermally with the aim to prepare a nano-hybrid coating for controlled release application (Scheme 2). Scheme 2. Schematic representation of the application of the G-PNPA sol on cotton surface and the 177 Scheme 2. Schematic representation of the application of the G-PNPA sol on cotton surface and the 177 Scheme 2. Schematic representation of the application of the G-PNPA sol on cotton surface and the formation of the coating xerogel. 178 formation of the coating xerogel. 178 formation of the coating xerogel. 3.2. Sol NMR Characterization 179 3.2. Sol NMR characterization 179 3.2. Sol NMR characterization A reaction mixture relative to the G-PNPA sol as obtained in methanol for coating application, 180 A reaction mixture relative to the G-PNPA sol as obtained in methanol for coating application, 180 A reaction mixture relative to the G-PNPA sol as obtained in methanol for coating application, has been achieved in situ (1:0.1 = [GPTES]:[PNPA] molar ratio) in methanol-d and characterized by 181 has been achieved in situ (1:0.1=[GPTES]:[PNPA] molar ratio) in methanol-d4 and char 4 acterized by 181 has been 1 achieved in situ (1:0.1=[GPTES]:[PNPA] molar ratio) in methanol-d4 and char 1 acterized by 1 1 182 meansmea of ns of H one- H one- and and two-dimensional two-dimensional NM NMR R spectro spectrsoscopy copy. Fig . u Figur re 1 shows e 1 shows the H N the MR H sp NMR ectra as spectra 1 1 182 means of H one- and two-dimensional NMR spectroscopy. Figure 1 shows the H NMR spectra as 183 recorded at time zero and after 24 h (in methanol-d4 at 298 K, 300 MHz). The comparison of the as recorded at time zero and after 24 h (in methanol-d at 298 K, 300 MHz). The comparison of the 183 recorded at time zero and after 24 h (in methanol-d4 at 298 K, 300 MHz). The comparison of the 184 aliphatic regions of the H NMR spectra of the reaction mixtures recorded at different times clearly aliphatic regions of the H NMR spectra of the reaction mixtures recorded at di erent times clearly 184 aliphatic regions of the H NMR spectra of the reaction mixtures recorded at different times clearly 185 reveal the presence of the protonic pattern expected for the diol/PEO silylated (red squares in Figure reveal the presence of the protonic pattern expected for the diol/PEO silylated (red squares in Figure 1) 185 reveal the presence of the protonic pattern expected for the diol/PEO silylated (red squares in Figure 186 1) derivatives and the starting GPTES (black squares in Figure 1, [20]) as shown in Scheme 1. In derivatives and the starting GPTES (black squares in Figure 1, [20]) as shown in Scheme 1. In particular, 186 187 1) der paivat rticul ive ar, the al s and tih pha e st tic regi arting G ons of PTE the S (b H NM lack s R qspec uaretra in s in Fi Figure gure 1 clear 1, [20]l) y sho as show w: (i) the pr n in Schem esence o e 1. f In the aliphatic regions of the H NMR spectra in Figure 1 clearly show: (i) the presence of the expected 188 the expected protonic pattern for the GPTES open ring derivative, bringing a hydroxyl and an ether 187 particular, the aliphatic regions of the H NMR spectra in Figure 1 clearly show: (i) the presence of protonic pattern for the GPTES open ring derivative, bringing a hydroxyl and an ether group bonded to 189 group bonded to two vicinal carbon Ce and Cf atoms (δ = 0.68, CH2a; 1.71, CH2b; 3.48, CH2c + CH2d + 188 the expected protonic pattern for the GPTES open ring derivative, bringing a hydroxyl and an ether two vicinal carbon C and C atoms ( = 0.68, CH ; 1.71, CH ; 3.48, CH + CH + CH ; 3.88 CH , 190 CH2f; 3.88 CH2e, red squares in lower spectrum) [30] (ii) the proton peaks relative to the starting e f 2a 2b 2c 2d 2f 2e 189 group bonded to two vicinal carbon Ce and Cf atoms (δ = 0.68, CH2a; 1.71, CH2b; 3.48, CH2c + CH2d + 191 GPTES in a decreased concentration (δ = 0.67, CH2a; 1.68, CH2b; 2.61+2.78, CH2f; 3.16, CH2e; 3.32 + 3.76, red squares in lower spectrum) [30] (ii) the proton peaks relative to the starting GPTES in a decreased 190 CH2f; 3.88 CH2e, red squares in lower spectrum) [30] (ii) the proton peaks relative to the starting 192 CH2d; 3.49, CH2c, black squares in upper spectrum); (iii) the presence of the upper-field methylene concentration ( = 0.67, CH ; 1.68, CH ; 2.61+2.78, CH ; 3.16, CH ; 3.32 + 3.76, CH ; 3.49, CH , 2a 2b 2f 2e 2d 2c 191 GPTES in a decreased concentration (δ = 0.67, CH2a; 1.68, CH2b; 2.61+2.78, CH2f; 3.16, CH2e; 3.32 + 3.76, 193 and the methyl proton resonances relative to free ethanol moieties, compared to those relative to the black squares in upper spectrum); (iii) the presence of the upper-field methylene and the methyl proton 192 CH2d; 3.49, CH2c, black squares in upper spectrum); (iii) the presence of the upper-field methylene 194 ethylic groups of GPTES (δ = 3.63, CH2, 1.19, CH3 vs 3.84, CH2, 1.22, CH3; cut signals in both spectra). resonances relative to free ethanol moieties, compared to those relative to the ethylic groups of GPTES 193 and the methyl proton resonances relative to free ethanol moieties, compared to those relative to the 194 ( e = th 3.63, ylic g CH roups , 1.19, of GP CH TES ( vsδ = 3.84, 3.63 CH , CH ,21.22, , 1.19, CH CH3 ; vs cut 3.signals 84, CH2, 1.22 in both , CH spectra). 3; cut signals in both spectra). 2 3 2 3 196 Figure 1. H NMR spectra relative to solutions of the G-PNPA sol, as obtained in methanol-d4 at 298 197 K, 300 MHz, at time zero (upper spectrum) and after 24 h reaction time in the presence of slight 198 amount of HCl (lower spectrum). Figure 1. H 1 NMR spectra relative to solutions of the G-PNPA sol, as obtained in methanol-d at 298 K, 197 Figure 1. H NMR spectra relative to solutions of the G-PNPA sol, as obtained in methanol-d4 at 298 300 MHz, at time zero (upper spectrum) and after 24 h reaction time in the presence of slight amount of 198 K, 300 MHz, at time zero (upper spectrum) and after 24 h reaction time in the presence of slight HCl (lower spectrum). 199 amount of HCl (lower spectrum). Appl. Sci. 2020, 10, 2287 6 of 13 Appl. Sci. 2020, 10, x FOR PEER REVIEW 6 of 13 Unfortunately, the long penta-decanoic protonic chain is buried under other signals, also due 200 Unfortunately, the long penta-decanoic protonic chain is buried under other signals, also due to to the strong molar ratio exceed of GPTES. The aromatic region shows the expected and unchanged 201 the strong molar ratio exceed of GPTES. The aromatic region shows the expected and unchanged pattern of broad signals for para-substituted phenyl ring of the PNPA molecule. 202 pattern of broad signals for para-substituted phenyl ring of the PNPA molecule. The H NMR experiments clearly show that the GPTES epoxy ring opening reaction by a suitable 203 The H NMR experiments clearly show that the GPTES epoxy ring opening reaction by a suitable nucleophilic group of the PNPA molecule is not occurring, as well as the formation of a stable ether 204 nucleophilic group of the PNPA molecule is not occurring, as well as the formation of a stable ether covalent bond. As previously shown [20], the stable encapsulation of the PNPA molecule into the 205 covalent bond. As previously shown [20], the stable encapsulation of the PNPA molecule into the PEO silylated GPTES derivative is most likely due to the formation of weak bonds (i.e., van der Waals 206 PEO silylated GPTES derivative is most likely due to the formation of weak bonds (i.e., van der Waals or electrostatic) between the polymerized GPTES (i.e., ether oxygen and hydroxyl group) and the 207 or electrostatic) between the polymerized GPTES (i.e., ether oxygen and hydroxyl group) and the N- N-Palmitoyl-(4-nitro-phenyl)-amine (i.e., nitrogen, oxygen, long alkyl chain, phenyl group). 208 Palmitoyl-(4-nitro-phenyl)-amine (i.e., nitrogen, oxygen, long alkyl chain, phenyl group). 3.3. ATR FT-IR 209 3.3. ATR FT-IR FT-IR spectra of untreated and treated cotton fabrics were analyzed after the normalization at 1362 210 FT-IR spectra of untreated and treated cotton fabrics were analyzed after the normalization at cm , absorption band relative to the CH bending of cellulose. In Figure 2, FT-IR of CO untreated -1 211 1362 cm , absorption band relative to the CH bending of cellulose. In Figure 2, FT-IR of COL untreated and treated samples with GPTES sol and G-PNPA sol (CO _UT, CO _GPTES and CO _G-PNPA, L L L 212 and treated samples with GPTES sol and G-PNPA sol (COL_UT, COL_GPTES and COL_G-PNPA, respectively) are reported and compared with those relative to CO untreated and treated fabrics 213 respectively) are reported and compared with those relative to COH untreated and treated fabrics with the same solutions (CO _UT, CO _GPTES and CO _G-PNPA, respectively). In particular, in all H H H 214 with the same solutions (COH_UT, COH_GPTES and COH_G-PNPA, respectively). In particular, in all spectra, it is possible to distinguish clearly the characteristic absorption bands relative to cellulose 1 1 215 spectra, it is possible to distinguish clearly the characteristic absorption bands relative to cellulose moieties, such as: the broad bands around to 3331 cm and 2894 cm (stretching mode of OH and CH, ₋1 ₋1 1 1 216 moieties, such as: the broad bands around to 3331 cm and 2894 cm (stretching mode of OH and respectively), and the absorption bands between 1097 cm and 895 cm relative to the asymmetric ₋1 ₋1 217 CH, respectively), and the absorption bands between 1097 cm and 895 cm relative to the in-plane ring stretch and to C–O stretch and asymmetric out-of-phase ring stretch (C –O–C ) [31]. 1 4 218 asymmetric in-plane ring stretch and to C–O stretch and asymmetric out-of-phase ring stretch (C1– In particular, in the inset in Figure 2A,B the presence of a silica coating is evident through the increase 1 1 219 O–C4) [31]. In particular, in the inset in Figure 2A–B the presence of a silica coating is evident through of the bands in the range 1145 cm –895 cm for the CO , assigned to the asymmetric stretching of ₋1 ₋1 1 1 220 the increase of the bands in the range 1145 cm –895 cm for the COL, assigned to the asymmetric the -Si–O–Si, and in the range between 995 cm –760 cm for the CO , due to the Si–O–Si absorption ₋1 ₋1 1 1 221 stretching of the -Si–O–Si, and in the range between 995 cm –760 cm for the COH, due to the Si–O– bending (852 cm ) and stretching (790 cm ). ₋1 ₋1 222 Si absorption bending (852 cm ) and stretching (790 cm ). Figure 2. FT-IR spectra of CO and CO untreated and treated with GPTES sol and G-PNPA sol (A L H 224 Figure 2. FT-IR spectra of COL and COH untreated and treated with GPTES sol and G-PNPA sol (A and B, respectively). (A) FT-IR spectra of CO untreated and treated with GPTES sol and G-PNPA sol; 225 and B, respectively).A) FT-IR spectra of COL untreated and treated with GPTES sol and G-PNPA sol; (B) FT-IR spectra of CO untreated and treated with GPTES sol and G-PNPA sol. 226 B) FT-IR spectra of COH untreated and treated with GPTES sol and G-PNPA sol. With the aim of investigating the chemical structure and interactions between silica precursor 227 With the aim of investigating the chemical structure and interactions between silica precursor and antioxidant molecule without the interference of the intense absorption bands of cotton fabrics, 228 and antioxidant molecule without the interference of the intense absorption bands of cotton fabrics, the FT-IR spectra of each sol was carried out on the pure xerogel. The latter was obtained by depositing 229 the FT-IR spectra of each sol was carried out on the pure xerogel. The latter was obtained by 230 depositing a few drops of each solution onto optical glass slides further subjected to a thermal 231 treatment (100 °C) to remove the solvent [26]. Indeed, by analyzing the FT-IR spectra of PNPA, it was Appl. Sci. 2020, 10, x FOR PEER REVIEW 7 of 13 232 possible to identify the characteristic peaks in order to establish its interaction with the GPTES sol. 233 Spectra of the GPTES sol (Figure 3, green line) clearly shows the formation of the inorganic network Appl. Sci. 2020, 10, 2287 7 of 13 ₋1 234 due to the absorption bands relative to: asymmetric (1093–1010 cm ) and symmetric stretching of Si– ₋1 ₋1 235 O–Si (756 cm ) and its bending mode (850 cm ) [17,18,20]. Furthermore, the absorption bands at a few drops of each ₋1 solution ₋1 onto optical glass ₋1 slides further subjected to a thermal treatment (100 C) 236 3072–3000 cm , 1255 cm and 906–850 cm were assigned to asymmetric and symmetric C–H stretch, to remove the solvent [26]. Indeed, by analyzing the FT-IR spectra of PNPA, it was possible to identify 237 ring breathing, as well as the asymmetric and symmetric ring deformation, respectively [17,18], the characteristic peaks in order to establish its interaction with the GPTES sol. Spectra of the GPTES 238 indicating that some unopened epoxy ring remain in GPTES sol. sol (Figure 3, green line) clearly shows the formation of the inorganic network due to the absorption 239 These peaks relative to the GPTES sol are also evidenced in the sol containing PNPA (Figure 3, 1 1 bands relative to: asymmetric (1093–1010 cm ) and symmetric stretching of Si–O–Si (756 cm ) and its 240 black line), in which the main characteristic absorption bands of the antioxidant molecules are 1 1 1 bending mode (850 cm ) [17,18,20]. Furthermore, the absorption bands at 3072–3000 cm , 1255 cm 241 present. As shown in Figure 2 (red line), PNPA is featured by the asymmetric and symmetric CH2 ₋1 and 906–850 cm were assigned to asymmetric and symmetric C–H stretch, ring breathing, as well as 242 stretching mode of alkyl chain (2916 and 2849 cm , respectively) with relative bending (1470–1458 the asymmetric ₋1 and symmetric ring deformation, respectively [17,18], indicating₋1 that some unopened 243 cm ), the C=O and C–N stretching of the secondary amide (1737 and 3075 cm , respectively) and the ₋1 epoxy ring remain in GPTES sol. 244 C–N stretching mode (1596 cm ) [32]. Figure 3. FT-IR spectra of PNPA, GPTES sol and G-PNPA sol. 246 Figure 3. FT-IR spectra of PNPA, GPTES sol and G-PNPA sol. These peaks relative to the GPTES sol are also evidenced in the sol containing PNPA (Figure 3, 247 3.4. Morphological characterizations black line), in which the main characteristic absorption bands of the antioxidant molecules are present. As shown in Figure 2 (red line), PNPA is featured by the asymmetric and symmetric CH stretching 248 All untreated and treated cotton samples were investigated by SEM and AFM microscopy, in 1 1 mode of alkyl chain (2916 and 2849 cm , respectively) with relative bending (1470–1458 cm ), 249 order to characterize the morphology of the coated textile fabric and to underline structural the C=O and C–N stretching of the secondary amide (1737 and 3075 cm , respectively) and the C–N 250 differences before and after the coating application. stretching mode (1596 cm ) [32]. 251 SEM analysis shows that the two analyzed tissues have two different weaves: COH_UT samples 252 have a larger weave than COL_UT ones, and the fibers appear less ordered compared with COL_UT 3.4. Morphological Characterizations 253 ones and more threadbare (compare Figure 4a and 4b). Both samples do not show modifications after All untreated and treated cotton samples were investigated by SEM and AFM microscopy, in order to characterize the morphology of the coated textile fabric and to underline structural di erences before and after the coating application. Appl. Sci. 2020, 10, 2287 8 of 13 SEM analysis shows that the two analyzed tissues have two di erent weaves: CO _UT samples have a larger weave than CO _UT ones, and the fibers appear less ordered compared with CO _UT ones L L and more threadbare (compare Figure 4a,b). Both samples do not show modifications after treatment Appl. Sci. 2020, 10, x FOR PEER REVIEW 8 of 13 Appl. Sci. 2020, 10, x FOR PEER REVIEW 8 of 13 and the morphology appears unchanged also at higher magnification (Figure 5). This demonstrates 254 that, trea after tment a treatment, nd the morphol no changes ogy at appears uncha micrometer scale nged a occur lso .at higher magnification (Figure 5). This 254 treatment and the morphology appears unchanged also at higher magnification (Figure 5). This 255 demonstrates that, after treatment, no changes at micrometer scale occur. 255 demonstrates that, after treatment, no changes at micrometer scale occur. 257 257 Figure 4. Figure 4. SE SEM analysis M analysis of of invest investigated igated samples: samples: CO CO H H_UT ( _UT ( aa), CO ), CO LL_UT ( _UT ( b b),), CO CO H H_GPTES ( _GPTES ( cc ), ), Figure 4. SEM analysis of investigated samples: CO _UT (a), CO _UT (b), CO _GPTES (c), H L H 258 258 CO CO LL _GPTES ( _GPTES ( d d ), CO ), CO H H _G-PNPA ( _G-PNPA ( ee ), CO ), CO LL _G-PNPA ( _G-PNPA ( ff ). ). CO _GPTES (d), CO _G-PNPA (e), CO _G-PNPA (f). L H L 260 260 Figure 5. Figure 5. SEM SEM analysis of analysis of inv inveestigated stigated samples at samples at higher magnification: higher magnification: CO CO H H_UT _UT ( ( aa), CO ), CO LL_UT ( _UT ( b b ), ), Figure 5. SEM analysis of investigated samples at higher magnification: CO _UT (a), CO _UT (b), H L 261 261 CO CO H H _GPTES ( _GPTES ( cc ), CO ), CO LL _GPTES ( _GPTES ( d d ), CO ), CO H H _G-PNPA ( _G-PNPA ( ee ),), CO CO LL _G- _G- P P NPA ( NPA ( ff ). ). CO _GPTES (c), CO _GPTES (d), CO _G-PNPA (e), CO _G-PNPA (f). H L H L 262 262 EDS EDS an analy alyssis is shows shows S Sii pe peak ak only only in in s saamples t mples trreeaatteedd wit withh GPTE GPTESS (CO (CO H H_G _GPT PTEESS, C , CO O LL _G _G PTE PTE SS ) ) 263 263 aa n n d su d su bs bs eq eq u u ee ntl ntl y y wi wi th th P P N N P P A A ( ( C C O O H H _G _G -P -P NPA NPA , C , C O O LL __ G G -PN -PN P P A) (Fi A) (Fi g g u u rr e e 66 , only two t , only two t rr ea ea ted sa ted sa mples mples aa rr e e 264 264 reported reported for for briefne briefne ss, bec ss, bec aa use the use the othe othe r ones exh r ones exh ii bi bi tt ed ed a a sim sim ii lar lar spectrum). Th spectrum). Th e other e other peak peak s s refer refer to to Appl. Sci. 2020, 10, 2287 9 of 13 EDS analysis shows Si peak only in samples treated with GPTES (CO _GPTES, CO _GPTES) Appl. Sci. 2020, 10, x FOR PEER REVIEW 9 of 13 H L and subsequently with PNPA (CO _G-PNPA, CO _G-PNPA) (Figure 6, only two treated samples are H L 265 carbon, present in the analyzed tissues but also in graphite adhesive used for SEM analysis, oxygen, reported for briefness, because the other ones exhibited a similar spectrum). The other peaks refer to 266 present also in vapor-low vacuum atmosphere, and aluminum, derived from the SEM stub. carbon, present in the analyzed tissues but also in graphite adhesive used for SEM analysis, oxygen, 267 The mapping presented in Figure 6 (inset c* and d*) shows that distribution of Si element present also in vapor-low vacuum atmosphere, and aluminum, derived from the SEM stub. 268 (present in GPTES) is very uniform and no phase separation occurs. Figure 6. EDS analysis of investigated samples: CO _UT (a), CO _UT (b), CO _G-PNPA (c), 270 Figure 6. EDS analysis of investigated samples: COH_UTH (a), COL_UT (b L), COH_G-PNPA ( H c), COL_G- CO _G-PNPA (d), and mapping of CO _G-PNPA (inset c*) and CO _G-PNPA (inset d*). 271 PNPA L (d), and mapping of COH_G-PNPA ( H inset c*) and COL_G-PNPA (inset L d*). The mapping presented in Figure 6 (inset c* and d*) shows that distribution of Si element 272 3.5. AFM characterizations (present in GPTES) is very uniform and no phase separation occurs. 273 Figure 7 shows that all the studied sampled are characterized by the typical filamentary 274 structure 3.5. AFM of t Characterizations he tissue fibers on the nanoscale. Figure 7 shows that all the studied sampled are characterized by the typical filamentary structure of the tissue fibers on the nanoscale. Thanks to the high resolution achieved by the AFM technique, it is possible to notice that both the two sample pairs CO _GPTES (Figure 7c), CO _GPTES (Figure 7d) and CO _G-PNPA (Figure 7e), L H L CO _G-PNPA (Figure 7f) are rougher than the untreated tissues CO _UT (Figure 7a), CO _UT H L H (Figure 7b), indicating that the GPTES and PNPA intimately and homogeneously wrap the fibers. This result is in good agreement with the EDS Si mapping. In the lower right corner of Figure 7f, it is possible to observe the presence of a lack in the coating; the study of the line profiles in that area allows us to evaluate the thickness of the coating that ranges between 2.5 and 4 nm. 275 Appl. Sci. 2020, 10, x FOR PEER REVIEW 9 of 13 265 carbon, present in the analyzed tissues but also in graphite adhesive used for SEM analysis, oxygen, 266 present also in vapor-low vacuum atmosphere, and aluminum, derived from the SEM stub. 267 The mapping presented in Figure 6 (inset c* and d*) shows that distribution of Si element 268 (present in GPTES) is very uniform and no phase separation occurs. 270 Figure 6. EDS analysis of investigated samples: COH_UT (a), COL_UT (b), COH_G-PNPA (c), COL_G- 271 PNPA (d), and mapping of COH_G-PNPA (inset c*) and COL_G-PNPA (inset d*). 272 3.5. AFM characterizations Appl. Sci. 2020, 10, 2287 10 of 13 273 Figure 7 shows that all the studied sampled are characterized by the typical filamentary 274 structure of the tissue fibers on the nanoscale. Appl. Sci. 2020, 10, x FOR PEER REVIEW 10 of 13 276 Figure 7. AFM micrograph of COL_UT (a), COH_UT (b), COL_GPTES (c), COH_GPTES (d), COL_G- 277 PNPA (e), and COH_G-PNPA (f). 278 Thanks to the high resolution achieved by the AFM technique, it is possible to notice that both 279 the two sample pairs COL_GPTES (Figure 7c), COH_GPTES (Figure 7d) and COL_G-PNPA (Figure 280 7e), COH_G-PNPA (Figure 7f) are rougher than the untreated tissues COL_UT (Figure 7a), COH_UT 281 (Figure 7b), indicating that the GPTES and PNPA intimately and homogeneously wrap the fibers. 282 This result is in good agreement with the EDS Si mapping. In the lower right corner of Figure 7f, it is Figure 7. AFM micrograph of CO _UT (a), CO _UT (b), CO _GPTES (c), CO _GPTES (d), L H L H 283 possible to observe the presence of a lack in the coating; the study of the line profiles in that area CO _G-PNPA (e), and CO _G-PNPA (f). L H 284 allows us to evaluate the thickness of the coating that ranges between 2.5 and 4 nm. 3.6. PNPA in Vitro Di usion Studies 285 3.6. PNPA in vitro diffusion studies In vitro di usion studies on the developed cotton-based textiles were carried out with the aim of 286 In vitro diffusion studies on the developed cotton-based textiles were carried out with the aim evaluating their ability to release in a controlled manner the synthesized PEA derivative compared to a 287 of evaluating their ability to release in a controlled manner the synthesized PEA derivative compared standard solution of the molecule (Scheme 3). 288 to a standard solution of the molecule (Scheme 3). Scheme 3. Schematic representation on the PNPA controlled release from the functional sol–gel coated 290 Scheme 3. Schematic representation on the PNPA controlled release from the functional sol–gel cotton by stimuli e ect. 291 coated cotton by stimuli effect. In the performed experiments, Strat-M membranes were used as a synthetic alternative, which 292 In the performed experiments, Strat-M membranes were used as a synthetic alternative, which is predictive of the di usion process occurring through human skin. The studies involved two 293 is predictive of the diffusion process occurring through human skin. The studies involved two di erent textiles, such as CO _G-PNPA and CO _G-PNPA, prepared employing the obtained G-PNPA L H 294 different textiles, such as COL_G-PNPA and COH_G-PNPA, prepared employing the obtained G- functional sol. The obtained results are expressed as cumulative di used amount (%) and the di usion 295 PNPA functional sol. The obtained results are expressed as cumulative diffused amount (%) and the profiles for the tested items are reported in Figure 8. 296 diffusion profiles for the tested items are reported in Figure 8. 298 Figure 8. In vitro diffusion profiles. 299 The two G-PNPA-coated cotton textiles, COL_G-PNPA and COH_G-PNPA, show similar results 300 in the performed in vitro diffusion studies. In the case of the COL_G-PNPA sample, indeed, the 301 amount of released PNPA is equal to 5% within the first hour reaching the 48% and 66% in 6 and 24 302 h, respectively, while the COH_G-PNPA sample exhibits a value of 7% after the first hour achieving Appl. Sci. 2020, 10, x FOR PEER REVIEW 10 of 13 276 Figure 7. AFM micrograph of COL_UT (a), COH_UT (b), COL_GPTES (c), COH_GPTES (d), COL_G- 277 PNPA (e), and COH_G-PNPA (f). 278 Thanks to the high resolution achieved by the AFM technique, it is possible to notice that both 279 the two sample pairs COL_GPTES (Figure 7c), COH_GPTES (Figure 7d) and COL_G-PNPA (Figure 280 7e), COH_G-PNPA (Figure 7f) are rougher than the untreated tissues COL_UT (Figure 7a), COH_UT 281 (Figure 7b), indicating that the GPTES and PNPA intimately and homogeneously wrap the fibers. 282 This result is in good agreement with the EDS Si mapping. In the lower right corner of Figure 7f, it is 283 possible to observe the presence of a lack in the coating; the study of the line profiles in that area 284 allows us to evaluate the thickness of the coating that ranges between 2.5 and 4 nm. 285 3.6. PNPA in vitro diffusion studies 286 In vitro diffusion studies on the developed cotton-based textiles were carried out with the aim 287 of evaluating their ability to release in a controlled manner the synthesized PEA derivative compared 288 to a standard solution of the molecule (Scheme 3). 290 Scheme 3. Schematic representation on the PNPA controlled release from the functional sol–gel 291 coated cotton by stimuli effect. 292 In the performed experiments, Strat-M membranes were used as a synthetic alternative, which 293 is predictive of the diffusion process occurring through human skin. The studies involved two 294 different textiles, such as COL_G-PNPA and COH_G-PNPA, prepared employing the obtained G- 295 PNPA functional sol. The obtained results are expressed as cumulative diffused amount (%) and the Appl. Sci. 2020, 10, 2287 11 of 13 296 diffusion profiles for the tested items are reported in Figure 8. Figure 8. In vitro di usion profiles. 298 Figure 8. In vitro diffusion profiles. The two G-PNPA-coated cotton textiles, CO _G-PNPA and CO _G-PNPA, show similar results in L H 299 The two G-PNPA-coated cotton textiles, COL_G-PNPA and COH_G-PNPA, show similar results the performed in vitro di usion studies. In the case of the CO _G-PNPA sample, indeed, the amount of 300 in the performed in vitro diffusion studies. In the case of the COL_G-PNPA sample, indeed, the released PNPA is equal to 5% within the first hour reaching the 48% and 66% in 6 and 24 h, respectively, 301 amount of released PNPA is equal to 5% within the first hour reaching the 48% and 66% in 6 and 24 while the CO _G-PNPA sample exhibits a value of 7% after the first hour achieving the 53% and 73% 302 h, respectively, while the COH_G-PNPA sample exhibits a value of 7% after the first hour achieving at the time points of 6 and 24 h. On the other hand, the 14% of PNPA is released after the first hour from the control solution reaching the 69% and 89% at 6 and 24 h. The experimental data confirm the ability of both the developed textiles to release in a controlled way the synthesized PEA derivative. These results could be related to the rate-limiting steps in drug release reported in the literature [33,34]: the drug di usion within the polymer matrix and the rate of polymer swelling. Depending on the presence of sweat, simulated with the bu er solution in contact with the PNPA-treated fabric, the weak interactions between the treated fabric and the antioxidant molecule slowly disappear until the drug is completely released. The presence of the sol–gel matrix increases the bonding interactions between the network and the drug, slowing down its release. 4. Conclusions The N-Palmitoyl-(4-nitro-phenyl)-amine, PNPA, a PEA derivative that already showed good anti-inflammatory and antioxidant properties, was firmly entrapped in a sol–gel-based matrix obtained by polymerization reaction of the epoxy-alkoxysilane GPTES, as cross-linker compound. NMR studies run on the sol evidenced that the GPTES epoxy-ring opening and the subsequent polymerization give rise to a polyethylene oxide 3D network grafted on textile with the PNPA immobilized into it. After the textile drying and curing the xerogel was morphologically studied on the treated cotton samples by SEM and AFM microscopy, revealing that no changes in the fiber morphology occurred at the micrometer scale, and that GPTES and PNPA intimately and homogeneously wrap the fibers. Furthermore, SEM mapping revealed a uniform distribution of the silica-based coating on the cotton fibers. In vitro di usion studies were realized on the developed functionalized cotton-based textiles in order to check their ability to release the PEA derivative in a controlled manner in comparison to a standard molecule solution. As a matter of fact, this functional textile has been shown to be a suitable system for PNPA release, thanks to the chemical binding weakening of PNPA with the sol–gel polymer matrix by mean of medium e ect, thus opening the way to the design of similar functional hybrid coatings for biomedical application. Although parameters of sol particles (e.g., hydrodynamic radius and electrokinetic potential) as well as the porosity of systems were not investigated, the obtained results confirmed the potential of the nanoengineered procedure as a versatile method for preparing stable and tunable drug-releasing materials. The combination of the functionality and transparency provided by the hybrid coating with its easy processability could represent an innovative route to fabricate biomaterials for healthcare. Future work will focus on the comparison of silica sols characteristics with release properties of this delivery system. Appl. Sci. 2020, 10, 2287 12 of 13 Author Contributions: Conceptualization was done by M.S.S., G.R. and M.R.P. Investigation was performed by F.P., O.I.P., C.S., M.G.B., V.T., G.R., C.T., C.M., E.P., M.S.S., D.I., M.R.P. and D.D. Project administration was directed by M.S.S., G.R. and M.R.P. Resources were provided by F.P., O.I.P., C.S., M.G.B., V.T., G.R., C.T., C.M., E.P., M.S.S., D.I., M.R.P. and D.D. Supervision was taken care of by M.S.S., G.R. and M.R.P. Validation was carried out by F.P. and O.I.P. Visualization and original draft writing was done by M.S.S., G.R. and M.R.P. All authors have read and agreed to the published version of the manuscript. Funding: This research received no external funding. Acknowledgments: MURST: CNR and MIUR are gratefully acknowledged for financial support. Conflicts of Interest: The authors declare no conflict of interest. References 1. Langer, R. Drug delivery and targeting. Nature 1998, 392, 5–10. 2. Brouwers, J.R.B.J. 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Applied Sciences – Multidisciplinary Digital Publishing Institute

Published: Mar 27, 2020

References

  • Drug delivery and targeting
    Langer