First multi-reactive polysaccharide-based transurf to produce potentially biocompatible dextran-covered nanocapsules (original) (raw)
Related papers
Materials Research, 2014
Poly(2-(dimethylamino)ethylmethacrylate-b-methymethacrylate) (PDMAEMA-b-PMMA) poly(2-(dimethylamino)ethylmethacrylate-b-vinylcaprolactam-b-(2-(dimethylamino)ethyl methacrylate) (PDMAEMA-b-PVCL-b-PDMAEMA) and poly(vinylcaprolactam-b-(2-(dimethylamino) ethylmethacrylate-b-vinylcaprolactam) (PVCL-b-PDMAEMA-b-PVCL) block copolymers were obtained by reversible addition-fragmentation chain transfer (RAFT) polymerization, and the effect of the solution pH on the particle size was investigated. In the case of PDMAEMA-b-PMMA, PDMAEMA was first synthesized using 2-cyanoprop-2-yl dithiobenzoate (CPDB) as a chain transfer agent (CTA), which was subsequently used for the RAFT polymerization of MMA. The triblock copolymers were obtained using PDMAEMA or PVCL as macro-CTAs prepared using dibenzyl trithiocarbonate (DBTTC) as a bifunctional RAFT agent. The structure and formation of the copolymers was confirmed through 1 H NMR and SEC analysis. The particle size varied considerably depending on the pH of the aqueous solutions of copolymers indicating that these materials could be potential candidates for biomedical applications.
Nanomaterials, 2019
Polymerization through reversible addition-fragmentation chain-transfer (RAFT) polymerization has been extensively employed for the production of polymers with controlled molar mass, complex architectures and copolymer composition distributions intended for biomedical and pharmaceutical applications. In the present work, RAFT miniemulsion copolymerizations of methyl methacrylate with acrylic acid and methacrylic acid were conducted to prepare hydrophilic polymer nanoparticles and compare cell uptake results after bioconjugation with bovine serum albumin (BSA), used as a model biomolecule. Obtained results indicate that the RAFT agent 2-cyano-propyl-dithiobenzoate allowed for successful free radical controlled methyl methacrylate copolymerizations and performed better when methacrylic acid was used as comonomer. Results also indicate that poly(methyl methacrylate-co-methacrylic acid) nanoparticles prepared by RAFT copolymerization and bioconjugated with BSA were exceptionally well accepted by cells, when compared to the other produced polymer nanoparticles because cellular uptake levels were much higher for particles prepared in presence of methacrylic acid, which can probably be associated to its high hydrophilicity.
Conferring biodegradability to nanoparticles is vitally important when nanomedicine applications are being targeted, as this prevents potential problems with bioaccumulation of byproducts after delivery. In this work, dextran has been modified (and rendered hydrophobic) by partial acetalation. A solid state NMR method was first developed to fully characterize the acetalated polymers. In a subsequent synthetic step, RAFT functionality was attached via residual unmodified hydroxyl groups. The RAFT groups were then used in a living free radical polymerization reaction to control the growth of hydrophilic PEG-methacrylate chains, thereby generating amphiphilic comblike polymers. The amphiphilic polymers were then self-assembled in water to form various morphologies, including small vesicles, wormlike rods, and micellar structures, with PEG at the periphery acting as a nonfouling biocompatible polymer layer. The acetalated dextran nanoparticles were designed for potential doxorubicin (DOX) delivery application based on the premise that in the cell compartments (endosome, lysozome) the acetalated dextran would hydrolyze, destroying the nanoparticle structure, releasing the encapsulated DOX. In-vitro studies confirmed minimal cytotoxicity of the (unloaded) nanoparticles, even after 3 days, proving that the hydrolysis products from the acetal groups (methanol and acetone) had no observable cytotoxic effect. An intriguing initial result is reported that in vitro studies of DOX-loaded dextrannanoparticles (compared to free DOX) revealed an increased differential toxicity toward a cancer cell line when compared to a normal cell line. Efficient accumulation of DOX in a human neuroblastoma cell line (SY-5Y) was confirmed by both confocal microscopy and flow cytometry measurements. Furthermore, the time dependent release of DOX was monitored using fluorescence lifetime imaging microscopy (FLIM) in SY-5Y live cells. FLIM revealed bimodal lifetime distributions, showing the accumulation of both DOX-loaded dextran-nanoparticles and subsequent release of DOX in the living cells. From FLIM data analysis, the amount of DOX released in SY-5Y cells was found to increase from 35% to 55% when the incubation time increased from 3 h to 24 h.
Advanced Drug Delivery Reviews, 2015
RAFT-mediated polymerization, providing control over polymer length and architecture as well as facilitating post polymerization modification of end groups, has been applied to virtually every facet of biomedical materials research. RAFT polymers have seen particularly extensive use in drug delivery research. Facile generation of functional and telechelic polymers permits straightforward conjugation to many therapeutic compounds while synthesis of amphiphilic block copolymers via RAFT allows for the generation of selfassembled structures capable of carrying therapeutic payloads. With the large and growing body of literature employing RAFT polymers as drug delivery aids and vehicles, concern over the potential toxicity of RAFT derived polymers has been raised. While literature exploring this complication is relatively limited, the emerging consensus may be summed up in three parts: toxicity of polymers generated with dithiobenzoate RAFT agents is observed at high concentrations but not with polymers generated with trithiocarbonate RAFT agents; even for polymers generated with dithiobenzoate RAFT agents, most reported applications call for concentrations well below the toxicity threshold; and RAFT end-groups may be easily removed via any of a variety of techniques that leave the polymer with no intrinsic toxicity attributable to the mechanism of polymerization. The low toxicity of RAFT-derived polymers and the ability to remove end groups via straightforward and scalable processes make RAFT technology a valuable tool for practically any application in which a polymer of defined molecular weight and architecture is desired.
Macromolecules, 2007
We report a detailed kinetic study of the RAFT polymerization of methyl 6-O-methacryloyl-R-D-glucoside (a methacrylic ester-type glycomonomer) with the chain transfer agent (CTA) (4-cyanopentanoic acid)-4-dithiobenzoate and initiator 4,4′-azobis(4-cyanopentanoic acid) in homogeneous aqueous media. The influence of temperature, initiator and CTA concentration, molar mass of the CTA radical leaving group, and the presence of residual oxygen on the polymerization kinetics were investigated in comparison with corresponding conventional free radical polymerizations (i.e., with no CTA present). RAFT processes were characterized by an initial non-steady-state period, the length of which depended inversely on the radical flux in the system, and were found to proceed at a significantly slower rate than the corresponding conventional free radical polymerizations. Also, attainment of the steady-state coincided with complete consumption of the initial CTA. The use of a macromolecular CTA reduced the length of the non-steady-state period but, interestingly, did not eliminate it, and the duration of this period was still shown to depend inversely on the initial CTA to initiator ratio. To our knowledge, this is the first time that a non-steady-state period has been observed in a RAFT polymerization initiated by a macromolecular CTA. Finally, the results of this investigation were used as a guide for the preparation of a series of well-defined living glyco-oligomers (DP n ) 15-66, PDI ) 1.05-1.12) in high yield.
Macromolecules, 2007
We report a detailed kinetic study of the RAFT polymerization of methyl 6-O-methacryloyl-R-D-glucoside (a methacrylic ester-type glycomonomer) with the chain transfer agent (CTA) (4-cyanopentanoic acid)-4-dithiobenzoate and initiator 4,4′-azobis(4-cyanopentanoic acid) in homogeneous aqueous media. The influence of temperature, initiator and CTA concentration, molar mass of the CTA radical leaving group, and the presence of residual oxygen on the polymerization kinetics were investigated in comparison with corresponding conventional free radical polymerizations (i.e., with no CTA present). RAFT processes were characterized by an initial non-steady-state period, the length of which depended inversely on the radical flux in the system, and were found to proceed at a significantly slower rate than the corresponding conventional free radical polymerizations. Also, attainment of the steady-state coincided with complete consumption of the initial CTA. The use of a macromolecular CTA reduced the length of the non-steady-state period but, interestingly, did not eliminate it, and the duration of this period was still shown to depend inversely on the initial CTA to initiator ratio. To our knowledge, this is the first time that a non-steady-state period has been observed in a RAFT polymerization initiated by a macromolecular CTA. Finally, the results of this investigation were used as a guide for the preparation of a series of well-defined living glyco-oligomers (DP n ) 15-66, PDI ) 1.05-1.12) in high yield.
PMMA-grafted dextran glycopolymers by atom transfer radical polymerization
Journal of Polymer Science Part A: Polymer Chemistry, 2008
The four-step synthesis of amphiphilic glycopolymers associating dextran as backbone and poly(methyl methacrylate) (PMMA) as grafts is reported, using the ''grafting from'' strategy. In the first step, the dextran OH functions were partially acetylated. The second step consisted in linking initiator groups by reaction of 2-bromoisobutyryl bromide (B i BB) with the unprotected OH functions. Third, the atom transfer radical polymerization (ATRP) of methyl methacrylate was carried out in DMSO from the resulting dextran derivative used as a macroinitiator. Finally, the cleavage of the acetate groups led to the expected glycopolymers. Careful attention was given both to the copolymer structure and the control of polymerization. PMMA grafts were analyzed by SEC-MALLS after their deliberate cleavage from the backbone to evidence a controlled polymerization. Moreover, the mildness of the final deprotection conditions was proved to ensure acetate cleavage without either degrading dextran backbone and PMMA grafts or cleaving grafts from dextran backbone.
Polímeros Ciência e Tecnologia, 2014
Tamoxifen (TXF) is currently the only hormonal agent used for treatment of breast cancer. Although very effective, TXF presents low solubility in water, which affects its absorption and bioavailability. A common strategy to overcome this barrier is the formulation of a drug delivery system (DDS) in order to increase the drug stability and improve the treatment effectiveness. Reversible addition-fragmentation chain transfer (RAFT) polymerization is the most versatile method of controlled/living radical polymerization (CLRP), allowing for synthesis of well-defined polymers and being adapted to a wide range of polymerization systems. Miniemulsion polymerization is a dispersed system that is commonly used to prepare nanoparticles (NP) with 50 to 500 nm of diameter. The aim of this work was to evaluate the effect of the in situ incorporation of TXF during miniemulsion conventional and RAFT polymerizations, using methyl methacrylate (MMA) as monomer. Although the in situ addition of TXF promoted a slight reduction of the reaction rate, it did not affect the final particle size distribution of the latex or the molecular weight control exerted by the RAFT agent. The obtained results suggest that in situ incorporation of TXF during the synthesis of polymer NP via RAFT polymerization allows for production of a polymer DDS for different uses, such as the breast cancer treatment.
2008
The controlled synthesis and characterization of a range of stimuli responsive cationic terpolymers containing varying amounts of N-isopropylacrylamide (NIPAM), 3-(methylacryloylamino)propyl trimethylammonium chloride (MAPTAC), and poly(ethylene glycol)monomethyl methacrylate (PEGMA) is presented. The terpolymers were synthesized using reversible addition-fragmentation chain transfer (RAFT) polymerization. Compositions of the terpolymers determined using 1 H NMR were in close agreement to the theoretical values determined from the monomer feed ratios. GPC-MALLS was used to analyze the molecular weight characteristics of the polymers, which were found to have low polydispersities (M w /M n 1.1-1.4). The phase transitions were studied as a function of PEGMA and NIPAM content using temperature controlled 1 H NMR and turbidity measurements (UV-Vis). The relationship between thermal stability and the comonomer ratio of the polymers was measured using thermogravimetric analysis (TGA). Protein interaction studies were performed to determine the suitability of the polymers for biological applications. V V C 2008 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 46: 4021-4029, 2008