Poly(N-vinylcaprolactam)-Gold Nanorods-5 Fluorouracil Hydrogels: In the Quest of a Material for Topical Therapies against Melanoma Skin Cancer.

Chemically crosslinked hydrogels based on poly(N-vinylcaprolactam) (PNVCL) were synthetized by a photoinitiated chemical method. A galactose-based monomer, 2-lactobionamidoethyl methacrylate (LAMA), and N-vinylpyrrolidone (NVP) were added with the aim to improve the physical and chemical properties of hydrogels. The effects of both comonomers on the swelling ratio (Q), volume phase transition temperature (VPTT), glass transition temperature (Tg), and Young's moduli by mechanical compression below and above the VPTT were studied. Gold nanorods (GNRDs) and 5-fluorouracil (5FU) were embedded into the hydrogels, to study the drug release profiles with and without the excitation of GNRDs by irradiation in the near-infrared region (NIR). Results showed that the addition of LAMA and NVP increased the hydrogels' hydrophilicity, elasticity, and VPTT. The loading of GNRDs in the hydrogels changed the release rate of 5FU when irradiated intermittently with an NIR laser. The present study reports on the preparation of a hydrogel-based platform of PNVCL-GNRDs-5FU as a potential hybrid anticancer hydrogel for chemo/photothermal therapy that could be applied against skin cancer for topical 5FU delivery.

NVCL-Based Hydrogels and Composites for Biomedical Applications: Progress in the Last Ten Years.

Hydrogels consist of three-dimensionally crosslinked polymeric chains, are hydrophilic, have the ability to absorb other molecules in their structure and are relatively easy to obtain. However, in order to improve some of their properties, usually mechanical, or to provide them with some physical, chemical or biological characteristics, hydrogels have been synthesized combined with other synthetic or natural polymers, filled with inorganic nanoparticles, metals, and even polymeric nanoparticles, giving rise to composite hydrogels. In general, different types of hydrogels have been synthesized; however, in this review, we refer to those obtained from the thermosensitive polymer poly(N-vinylcaprolactam) (PNVCL) and we focus on the definition, properties, synthesis techniques, nanomaterials used as fillers in composites and mainly applications of PNVCL-based hydrogels in the biomedical area. This type of material has great potential in biomedical applications such as drug delivery systems, tissue engineering, as antimicrobials and in diagnostic and bioimaging.

Film Forming Nanogels for Needle-Free Transdermal Vaccination.

Transcutaneous immunization (TCI) provides a valuable alternative approach to conventional vaccination because of the high accessibility and the exceptional immunological characteristics of the skin, but its application is limited by the low permeability of the stratum corneum. Although nanogels (NGs) have proven to enhance skin penetration of macromolecules with minimum damage, their use in TCI remains almost unexplored. In this context, this article evaluates the performance of novel film-forming NGs (FF-NGs) as TCI. This TCI platform consists of NGs with multilobular morphology that positively combines the properties of cross-linked poly(N-vinylcaprolactam), like thermoresponsiveness and the ability to load and release a cargo, with the film-forming capacity of low Tg lobes. FF-NGs and formed films are characterized at different levels. Formed films show to be able to uniformly load an antigenic protein and release it with a profile depending on the temperature and on their FF-NGs content. In vivo studies have demonstrated that FF-NGs promote the penetration of not only an antigenic protein, but also an adjuvant until the immunocompetent area of skin, generating an adjuvant-dependent specific immune response. Finally, this study provides a successful proof of concept that FF-NGs can be a powerful tool for the transcutaneous release of complex formulations.

Effective End-Group Modification of Star-Shaped PNVCL from Xanthate to Trithiocarbonate Avoiding Chemical Crosslinking.

In this study, six-arm star-shaped poly(N-vinylcaprolactam) (PNVCL) polymers prepared by reversible addition-fragmentation chain transfer (RAFT) polymerization were subjected to aminolysis reaction using hexylamine. Chemically crosslinked gels or highly end-functionalized star polymers can be obtained depending mainly on the type of solvent used during the transformation of the RAFT functional group. An increase in the viscosity of the solution was observed when the aminolysis was carried out in THF. In contrast, when the reaction was conducted in dichloromethane, chain-end thiol (PNVCL)6 star polymers could be obtained. Moreover, when purified (PNVCL-SH)6 star polymers are in contact with THF, the gelation occurs in just a few minutes, with an obvious increase in viscosity, to form physical gels that become chemically crosslinked gels after 12 h. Interestingly, when purified (PNVCL-SH)6 star polymers were stirred in distilled water, even at high aqueous solution concentration (40 mg/mL), there was no increase in the viscosity or gelation, and no evident gels were observed. The analysis of the hydrodynamic diameter (Dh) by dynamic light scattering (DLS) did not detect quantifiable change even after 4 days of stirring in water. On the other hand, the thiol groups in the (PNVCL-SH)6 star polymers were easily transformed into trithiocarbonate groups by addition of CS2 followed by benzyl bromide as demonstrated by UV-Vis spectroscopical analysis and GPC. After the modification, the (PNVCL)6 star polymers exhibit an intense yellow color typical of the absorption band of trithiocarbonate group at 308 nm. To further demonstrate the highly effective new trithiocarbonate end-functionality, the PNVCL polymers were successfully chain extended with N-isopropylacrylamide (NIPAM) to form six-arm star-shaped PNIPAM-b-PNVCL block copolymers. Moreover, the terminal thiol end-functionality in the (PNVCL-SH)6 star polymers was linked via disulfide bond formation to l-cysteine to further demonstrate its reactivity. Zeta potential analysis shows the pH-responsive behavior of these star polymers due to l-cysteine end-functionalization. By this using methodology and properly selecting the solvent, various environment-sensitive star polymers with different end-groups could be easily accessible.

Small interfering RNA for cancer treatment: overcoming hurdles in delivery.

In many ways, cancer cells are different from healthy cells. A lot of tactical nano-based drug delivery systems are based on the difference between cancer and healthy cells. Currently, nanotechnology-based delivery systems are the most promising tool to deliver DNA-based products to cancer cells. This review aims to highlight the latest development in the lipids and polymeric nanocarrier for siRNA delivery to the cancer cells. It also provides the necessary information about siRNA development and its mechanism of action. Overall, this review gives us a clear picture of lipid and polymer-based drug delivery systems, which in the future could form the base to translate the basic siRNA biology into siRNA-based cancer therapies.

Different Strategies for the Preparation of Galactose-Functionalized Thermo-Responsive Nanogels with Potential as Smart Drug Delivery Systems.

Different synthetic strategies were tested for the incorporation of galactose molecules on thermoresponsive nanogels owing to their affinity for receptors expressed in cancer cells. Three families of galactose-functionalized poly(N-vinylcaprolactam) nanogels were prepared with the aim to control the introduction of galactose-moieties into the core, the core-shell interface and the shell. First and second of the above mentioned, were prepared via surfactant free emulsion polymerization (SFEP) by a free-radical mechanism and the third one, via SFEP/reversible addition-fragmentation chain transfer (RAFT) polymerization. Synthetic recipes for the SFEP/free radical method included besides N-vinylcaprolactam (NVCL), a shell forming poly(ethylene glycol) methyl ether methacrylate (PEGMA), while the galactose (GAL) moiety was introduced via 6-O-acryloyl-1,2,:3,4-bis-O-(1-methyl-ethylidene)-α-D-galactopiranose (6-ABG, protected GAL-monomer): nanogels I, or 2-lactobionamidoethyl methacrylate (LAMA, GAL-monomer): nanogels II. For the SFEP/RAFT methodology poly(2-lactobionamidoethyl methacrylate) as GAL macro-chain transfer agent (PLAMA macro-CTA) was first prepared and on a following stage, the macro-CTA was copolymerized with PEGMA and NVCL, nanogels III. The crosslinker ethylene glycol dimethacrylate (EGDMA) was added in both methodologies for the polymer network construction. Nanogel's sizes obtained resulted between 90 and 370 nm. With higher content of PLAMA macro-CTA or GAL monomer in nanogels, a higher the phase-transition temperature (TVPT) was observed with values ranging from 28 to 46 °C. The ρ-parameter, calculated by the ratio of gyration and hydrodynamic radii from static (SLS) and dynamic (DLS) light scattering measurements, and transmission electron microscopy (TEM) micrographs suggest that core-shell nanogels of flexible chains were obtained; in either spherical (nanogels II and III) or hyperbranched (nanogels I) form.

Synthesis and Self-Assembly of Poly(N-Vinylcaprolactam)-b-Poly(ε-Caprolactone) Block Copolymers via the Combination of RAFT/MADIX and Ring-Opening Polymerizations.

Well-defined amphiphilic, biocompatible and partially biodegradable, thermo-responsive poly(N-vinylcaprolactam)-b-poly(ε-caprolactone) (PNVCL-b-PCL) block copolymers were synthesized by combining reversible addition-fragmentation chain transfer (RAFT) and ring-opening polymerizations (ROP). Poly(N-vinylcaprolactam) containing xanthate and hydroxyl end groups (X-PNVCL-OH) was first synthesized by RAFT/macromolecular design by the interchange of xanthates (RAFT/MADIX) polymerization of NVCL mediated by a chain transfer agent containing a hydroxyl function. The xanthate-end group was then removed from PNVCL by a radical-induced process. Finally, the hydroxyl end-capped PNVCL homopolymer was used as a macroinitiator in the ROP of ε-caprolactone (ε-CL) to obtain PNVCL-b-PCL block copolymers. These (co)polymers were characterized by Size Exclusion Chromatography (SEC), Fourier-Transform Infrared spectroscopy (FTIR), Proton Nuclear Magnetic Resonance spectroscopy (1H NMR), UV-vis and Differential Scanning Calorimetry (DSC) measurements. The critical micelle concentration (CMC) of the block copolymers in aqueous solution measured by the fluorescence probe technique decreased with increasing the length of the hydrophobic block. However, dynamic light scattering (DLS) demonstrated that the size of the micelles increased with increasing the proportion of hydrophobic segments. The morphology observed by cryo-TEM demonstrated that the micelles have a pointed-oval-shape. UV-vis and DLS analyses showed that these block copolymers have a temperature-responsive behavior with a lower critical solution temperature (LCST) that could be tuned by varying the block copolymer composition.

Chitosan microparticles embedded with multi-responsive poly(N-vinylcaprolactam-co-itaconic acid-co-ethylene-glycol dimethacrylate)-based hydrogel nanoparticles as a new carrier for delivery of hydrophobic drugs.

In this paper, chitosan was used as protective agent for dual temperature-/pH-sensitive poly(N-vinylcaprolactam-co-itaconic acid-co-ethylene- glycol dimethacrylate)- based hydrogel nanoparticles (poly(NVCL-co-IA-co-EGDMA)) aiming avoid their undesirable colloidal destabilization at different conditions of body human tissues. Thus, poly(NVCL-co-IA-co-EGDMA) was embedded into chitosan and a new solid dispersion was prepared via spray-drying and ketoprofen was used as carrier. Two different sizes of hydrogel nanoparticles (120.6 nm and 185.9 nm) were evaluated and they exhibited a drug encapsulation efficiency of the 39.6% and 57.8%, respectively. The smaller nanoparticles showed to be faster for releasing of ketoprofen at pH 7.4 and 37 °C due to their larger surface area and higher swelling ability. Chitosan played a role of a secondary barrier for the ketoprofen diffusion, extending its release compared to hydrogel nanoparticles alone. Among two concentrations (40 wt% and 70 wt%) of hydrogel nanoparticles related to chitosan, the first one induced higher percentages of ketoprofen release: 74.2% against 64.6%. In addition, the interactions between chitosan matrix and poly(NVCL-co-IA-co-EGDMA) did not change the multi-responsive behavior of hydrogels, suggesting the chitosan was efficient for keeping integrity of nanoparticles hydrogels. Chitosan/poly(NVCL-co-IA-co-EGDMA) hybrid microparticles seems to be a promising new carrier for release of hydrophobic drugs, such as ketoprofen.

Synthesis and characterization of poly(N-vinylcaprolactam)-based spray-dried microparticles exhibiting temperature and pH-sensitive properties for controlled release of ketoprofen.

Poly(N-vinylcaprolactam) (PNVCL) and poly(N-vinylcaprolactam-co-acrylic acid) (poly(NVCL-co-AA)) were synthesized by solution-free radical polymerization and displayed thermo-responsive behavior, with lower critical solution temperatures (LCSTs) of 35 °C and 39 °C, respectively. The incorporation of AA unities made the poly(NVCL-co-AA) sensitive to both pH and temperature. They were exploited in this work in preparing microparticles loaded with ketoprofen via spray-drying to modulate the drug release rate by changing pH or temperature. The interaction between polymer and drug was studied using X-ray diffractometry, Raman spectrometry and scanning electron microscopy (SEM). The biocompatibility of pure polymers, free ketoprofen as well as the spray-dried particles was demonstrated in vitro by low cytotoxicity and a lack of nitric oxide production in macrophages at concentrations as high as 100 µg/ml. The release profile of ketoprofen was evaluated by in vitro assays at different temperatures and pH values. Drug diffusion out of PNVCL's hydrated polymer network is increased at temperatures below the LCST. However, when poly(NVCL-co-AA) was used as the matrix, the release of ketoprofen was primarily controlled by the pH of the medium. These results indicated that PNVCL and the novel poly(NVCL-co-AA) could be promising candidates for pH and temperature-responsive drug delivery systems.

Preparation of a Mini-Library of Thermo-Responsive Star (NVCL/NVP-VAc) Polymers with Tailored Properties Using a Hexafunctional Xanthate RAFT Agent.

A mini-library of star-shaped thermoresponsive polymers having six arms was prepared using a hexafunctional xanthate by reversible addition⁻fragmentation chain transfer (RAFT) polymerization. Star polymers with homopolymeric arms of poly(N-vinylcaprolactam) (PNVCL), copolymeric arms of poly(N-vinylcaprolactam-co-N-vinylpyrrolidone) (PNVCL-co-PNVP) and also arms of block copolymers of PNVCL-b-PVAc, (PNVCL-co-PNVP)-b-PVAc, and combinations of them changing the order of the block was achieved exploiting the R-RAFT synthetic methodology (or R-group approach), wherein the thiocarbonyl group is transferred to the polymeric chain end. Taking advantage of the RAFT benefits, the molecular weight of the star polymers was controlled (Mn = 11,880⁻153,400 g/mol) to yield star polymers of different sizes and lower critical solution temperature (LCST) values. Removing the xanthate group of the star polymers allowed for the introduction of specific functional groups at the ends of the star arms and resulted in an increase of the LCST values. Star PNVCL-b-PVAc diblock copolymers with PVAc contents of 5⁻26 mol % were prepared; the hydrophobic segment (PVAc) is located at the end of the star arms. Interestingly, when the PVAc content was 5⁻7 mol %, the hydrodynamic diameter (Dh) value of the aggregates formed in water was almost the same sa the Dh of the corresponding PNVCL star homopolymers. It is proposed that these star block copolymers self-assemble into single flowerlike micelles, showing great stability in aqueous solution. Star block copolymers with the PVAc hydrophobic block in the core of the star, such as PVAc-b-(PNVCL-co-PNVP), form micellar aggregates in aqueous solution with Dh values in the range from ~115 to 245 nm while maintaining a thermoresponsive behavior. Micellar aggregates of selected star polymers were used to encapsulate methotrexate (MTX) showing their potential in the temperature controlled release of this antineoplasic drug. The importance of the order in which each block constituent is introduced in the arms of the star polymers for their solution/aggregation behavior is demonstrated.

Radiation grafting of N-vinylcaprolactam onto nano and macrogels of chitosan: Synthesis and characterization.

The aim of this study was to synthesize chitosan hydrogels, in macro- and nano-size, grafted with N-vinylcaprolactam (NVCL) using gamma radiation, and evaluate their potential application as a drug delivery system, using 5-fluorouracil (5-FU) as a model drug. The effect of dose and monomer concentration in the grafting process was studied, and the materials were characterized by FTIR, TGA, DLS, SEM and AFM. Higher grafting percentages were observed for the nanogels system. Although both the grafted macro- and nanogels, (net-CS)-g-NVCL, showed a response to pH (4.75) and temperature (31-33°C), the nanogels showed a better swelling response to both stimuli because of their higher surface area. Both systems were able to load 5-FU in small amounts (2-3.5mgg-1) and the release was sustained for more than 12h, showing that the modified macro and nanogels can be a potential alternative for the administration of drugs.

Synthesis and characterization of stimuli-responsive polypropylene containing N-vinylcaprolactam and N-vinylimidazole obtained by ionizing radiation.

Polypropylene films were grafted with thermo-responsive N-vinylcaprolactam and pH-responsive N-vinylimidazole polymers by means of gamma radiation using pre-irradiation and direct methods, in order to functionalize the films with thermo- and/or pH-responsiveness. The dependence of grafting yield on parameters such as co-monomer concentration, pre-irradiation dose, temperature, and reaction time was evaluated. The samples were characterized by Fourier transform infrared and X-ray photoelectron spectroscopies, differential scanning calorimetry, thermogravimetric analysis, swelling studies in different solvents, and water contact angle. The grafted copolymers presented thermo- and pH-sensitiveness, highlighting their potential as advanced biomaterials, capable of providing adequate environment for hosting and sustained release of antimicrobial drugs bearing cationic moieties, such as groups of diclofenac, while still exhibiting good cytocompatibility.

Effect of the molecular architecture on the thermosensitive properties of chitosan-g-poly(N-vinylcaprolactam).

A series of thermoresponsive copolymers based on chitosan-g-poly(N-vinylcaprolactam) were synthesized by amidation reaction using 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride as coupling reagent. The effect of molecular architecture on the thermoresponsive properties of the graft copolymers solutions was studied by varying the chain length of the grafted poly(N-vinylcaprolactam), PVCL, (in the range from 4 to 26 kDa) and the spacing between grafted chains onto the chitosan backbone. The most interesting characteristic of these copolymers is their solubility in water at temperatures below their lower critical solution temperature (LCST). These solutions presented a LCST between 36 and 44 °C, which decreases with the spacing and length of grafted PVCL chains onto the chitosan backbone, in contrast with the limited decrease of the LCST of PVCL above a critical M¯n value around 18 kDa. This behavior offers tangible possibilities for the preparation and application of sensitive bioactive formulations and "smart" drug delivery systems.