Amphiphilic Graft Polymers Research Articles

Surface Modification of Polycaprolactone Scaffold With Improved Biocompatibility and Controlled Growth Factor Release for Enhanced Stem Cell Differentiation

Polycaprolactone (PCL) has been widely used as a scaffold material for tissue engineering. Reliable applications of the PCL scaffolds require overcoming their native hydrophobicity and obtaining the sustained release of signaling factors to modulate cell growth and differentiation. Here, we report a surface modification strategy for electrospun PCL nanofibers using an azide-terminated amphiphilic graft polymer. With multiple alkylation and pegylation on the side chains of poly-L-lysine, stable coating of the graft polymer on the PCL nanofibers was achieved in one step. Using the azide-alkyne “click chemistry”, we functionalized the azide-pegylated PCL nanofibers with dibenzocyclooctyne-modified nanocapsules containing growth factor, which rendered the nanofiber scaffold with satisfied cell adhesion and growth property. Moreover, by specific immobilization of pH-responsive nanocapsules containing bone morphogenetic protein 2 (BMP-2), controlled release of active BMP-2 from the PCL nanofibers was achieved within 21 days. When bone mesenchyme stem cells were cultured on this nanofiber scaffold, enhanced ossification was observed in correlation with the time-dependent release of BMP-2. The established surface modification can be extended as a generic approach to hydrophobic nanomaterials for longtime sustainable release of multiplex signaling proteins for tissue engineering.

Amphiphilic graft polymer with reduction breakable main chain prepared via click polymerization and grafting onto

Amphiphilic graft polymer PSS-g-Pal/PEG with reduction breakable main chain was synthesized via click polymerization of dialkynyl (containing disulfide bond) and diazide (containing pendant diol) and one-pot grafting onto of hydrophobic palmitate (Pal) and hydrophilic methoxy poly(ethylene glycol) (PEG). PSS-g-Pal/PEG is able to form polymeric micelles by self-assembly in water via dialysis. Polymeric micelles are nano-sized spheres and the particle size is approximately 70 nm. Of note, polymeric micelles are reduction-responsive owing to the disulfide bonds in main chain of PSS-g-Pal/PEG. Therefore, polymeric micelles prepared from amphiphilic graft polymer PSS-g-Pal/PEG are able to fast release the drugs in the presence of the reducing agents such as DL-dithiothreitol (DTT).

Recent Advances in Amphiphilic Polymers as the Stabilizers of Colloidal Gold Nanoparticles

AbstractGold nanoparticles (AuNPs) exhibit high catalytic activity as catalysts and have potential applications in biomedicine. To prevent the aggregation of colloidal AuNPs, the stabilizers including organic small molecules, organic ligands, inorganic ligands, and polymers, are necessary to be added in the synthesis of colloidal AuNPs. Among these stabilizers, amphiphilic polymers have attracted significant attention from scientists in the development of polymerization and modification methods. To date, numerous efforts are employed to develop amphiphilic polymers as the stabilizers of colloidal AuNPs but are not well‐summarized yet. In this review, four parts (amphiphilic linear polymers, amphiphilic graft polymers, amphiphilic hyperbranched polymers, and amphiphilic dendrimers) according to the polymer architectures will be discussed. Comprehensive understanding of amphiphilic polymers that are used for stabilizing colloidal AuNPs is provided.

Biodegradable amphiphilic graft polymer synthesized via the combination of ring-opening polymerization (ROP) and atom transfer radical polymerization (ATRP)

The biodegradability of polyacrylate derivatives is of great importance to their applications in medical and biological science. Here we design a six-membered carbonate monomer 2-(2-bromoisobutyrylamido)trimethylene carbonate (BrTMC) with an atom transfer radical polymerization (ATRP) initiating group 2-bromoisobutyryl. Ring-opening polymerization (ROP) of BrTMC and 2,2-dimethyltrimethylene carbonate (DTC) was carried out to synthesize copolycarbonate P(BrTMC-DTC), which further initiated ATRP of hydroxyethyl methacrylate (HEMA) to prepare biodegradable amphiphilic graft polymer P(BrTMC-DTC)-g-PHEMA. P(BrTMC-DTC)-g-PHEMA was able to form the micelles by self-assembly.

Synthesis of an amphiphilic graft copolymer bearing a hydrophilic poly(acrylate acid) backbone for drug delivery of methotrexate

This article reports the synthesis of a PAA-g-PLA amphiphilic graft polymer, which could self-assemble into large compound micelles in aqueous media for sustained release of MTX.

Surface-Functionalized Biodegradable Nanoparticles Consisting of Amphiphilic Graft Polymers Prepared by Radical Copolymerization of 2-Methylene-1,3-Dioxepane and Macromonomers.

Biodegradable polyester-based nanoparticles were prepared by the precipitation of amphiphilic graft copolymers, which were prepared by the ring-opening radical copolymerization of 2-methylene-1,3-dioxepane (MDO) and amphiphilic macromonomers. The diameter of the nanoparticles was controlled by the degree of grafting and the molecular weight of the grafting oligomer. PMDO-g-poly(ethylene glycol) nanoparticles were degraded by the alkaline hydrolysis of the polyester backbone. Although the colloidal stability of nanoparticles was retained due to the reorientation of the PEG chains during hydrolysis, the size of the nanoparticles decreased with increasing hydrolysis time. We also prepared PMDO-g-poly(N-isopropylacrylamide) nanoparticles, which show aggregation in response to increasing temperature.

The preparation and characterization of micelles from poly(γ-glutamic acid)-graft-poly(L-lactide) and the cellular uptake thereof.

Chemotherapy is a traditional therapeutic approach for the treatment of many solid tumors, but the poor solubility and low bioavailability of hydrophobic anti-cancer drugs greatly limit their applications. In this article, DOX-loaded micelles were fabricated based on an amphiphilic graft polymer composed of hydrophilic poly(γ-glutamic acid) (γ-PGA) and hydrophobic poly (L-lactide) (PLLA). The structure of the copolymers and the characteristic of the micelles were studied. The release profiles of doxorubicin as a model drug from the micelles were measured. Due to the protonation of the amino group of DOX and the conformational alteration of γ-PGA, the release of DOX from γ-PGA-g-PLLA micelle was faster in the acid condition, which is beneficial to tumor therapy. The cellular uptake of the DOX-loaded γ-PGA-g-PLLA micelle was proved to be a GGT-mediated process.

Synthesis, characterization, and drug delivery of amphiphilic poly{(lactic acid)-co-[(glycolic acid)-alt-(L-glutamic acid)]}-g-poly(ethylene glycol)

This paper discusses the use of a novel amphiphilic graft polymer poly{(lactic acid)-co-[(glycolic acid)-alt-(Lglutamic acid)]}-g-monomethyl poly(ethylene glycol) (PLGG-g-mPEG) as a drug carrier. PLGG was synthesized through the ring-opening polymerization of L-lactide (LLA) and (3s)-benzoxylcarbonylethyl-morpholine-2,5-dione (BEMD) using Sn(Oct)2 as a catalyst and it was subsequently deprotected via hydrogenolysis in the presence of Pd/C. A series of monomethyl poly(ethylene glycol) (PEG) with the molecular weights of 2,000, 1,100, and 500 were immobilized on the carboxyl groups of PLGG. These PEGylated graft derivatives were characterized using proton nuclear magnetic resonance spectra (1H NMR), Fourier transform infrared spectroscopy (FTIR), and gel permeation chromatography (GPC). The critical micelle concentrations (CMCs) of the amphiphilic copolymers were tested by the fluorescence probe technique and the CMCs were 2.3, 1.0, and 0.32 μg/mL, respectively. Transmission electronic microscopy (TEM) and dynamic light scattering (DLS) images revealed that the micelles were homogeneous spherical nanoparticles and the sizes of the micelles were distributed across a range of 80 to 22 nm. Anticancer drug doxorubicin (DOX) was loaded into the micelles. The in vitro release profiles showed that the sustaining release of the drugloaded micelles could last over 7 days. The in vitro cytotoxicity assay of the DOX-loaded micelles against HepG2 cells was assessed by methyl thiazolyl tetrazolium (MTT) assays. The results demonstrated that the drug-loaded micelles exhibited a high level of inhibition activity on cancer cells. The confocal microscopy images of HepG2 cells showed that DOX released from the micelles could be delivered into cell nuclei. PLGG-g-mPEG micelles are promising potential carriers for delivering anticancer drugs. Open image in new window

The microfluidity and dissolution of hydrogenated PC liposome anchored with alkyl grafted poly(amino acid)s

The stability of a polymer hybridized liposome (PHL) was examined with the microfluidic and thermal state of anchored alkyl chains, and with dissolution against deoxycholate (DOC). Poly(asparagine) grafted with octadecylamine (PAsn-g-C 18), poly(aspartic acid) grafted with octadecylamine (PAsp-g-C 18), and poly(aspartic acid) grafted with phytosphingosine (PAsp-g-PHS) were synthesized. The microfluidity of the membrane of the PHL was evaluated by fluorescence polarization of 1,6-diphenyl-1,3,5-hexatriene (DPH) and the phase transition temperature ( T c) was measured by differential scanning calorimetry (DSC). The membrane fluidity of liposomes was increased by the inclusion of amphiphilic graft polymers. The phase transition temperature of liposomes increased by the anchoring of PAsn-g-C 18, while the inclusion of PAsp-g-C 18 or PAsp-g-PHS lowered the T c. The surface charge of PHL of PAsn-g-C 18 was changed by the cationic lipid content. The structural stability of the PHL was affected by variation of the hydrophilic backbone or the hydrophobic moiety of the polymer and PHL of PAsn-g-C 18 was most stable against DOC. An increased degree of substitution of the graft copolymer led to better stability of the PHL. It was found that the polymer characteristics affect the physicochemical strength of the PHL structure, resulting in different degrees of stability enhancement.

Synthesis and characterization of an amphiphilic graft polymer and its potential as a pH-sensitive drug carrier

The synthesis and properties of a new pH-sensitive polymer Poly(ɛ-caprolactone) Grafted Poly(ethylene glycol) Based Poly(ß-amino ester) (PEGAE-g-PCL) are described here. The successful synthesis of the graft copolymer was confirmed by 1H NMR. The self-assemble behavior of the amphiphilic polymer was investigated using pyrene as a probe. Dynamic light scattering (DLS) showed that the polymeric micelles had a size of 60 nm at physiological pH and were responsive to pH. A spherical morphology was observed for the micelles using transmission electron microscopy (TEM). Zeta-potential measurement at different pH showed that the micelles were neutral at pH 7.4 and positively charged at lower pH. Doxorubicin (DOX) was used as a model drug and loaded in the micelles. The drug loaded micelles showed a slow and pH-dependant drug release behavior. The remaining hydroxyl groups on the main chain made it possible the further conjugation of imaging agents or targeting groups.

Chemosynthesis of Poly(ε-lysine)-Analogous Polymers by Microwave-Assisted Click Polymerization

Poly(ε-lysine) (ε-PL)-analogous click polypeptides with not only similar α-amino side groups but also similar main chain to ε-PL were chemically synthesized for the first time through click polymerization from aspartic (or glutamic)-acid-based dialkyne and diazide monomers. With microwave-assisting, the reaction time of click polymerization was compressed into 30 min. The polymers were fully characterized by NMR, ATR-FTIR, and SEC-MALLS analysis. The deprotected click polypeptides had similar pK(a) value (7.5) and relatively low cytotoxicity as ε-PL and could be used as substitutes of ε-PL in biomedical applications, especially in endotoxin selective removal. Poly(ethylene glycol) (PEG)-containing alternating copolymers with α-amino groups were also synthesized and characterized. After deprotection, the polymers could be used as functional gene vector with PEG shadowing system and NCA initiator to get amphiphilic graft polymers.

Preparation and characterization of thermosensitive and biodegradable PNDH- g-PLLA nanoparticles for drug delivery

A series of thermosensitive and biodegradable graft copolymers (PNDH- g-PLLA) were synthesized by the radical copolymerization of N-isopropylacrylamide, N,N-dimethylacrylamide and N-(hydroxymethyl)acrylamide, followed by the ring-opening polymerization of L-lactide. The molecular weight and chemical structure of these copolymers were determined by gel permeation chromatography (GPC), nuclear magnetic resonance ( 1H NMR) and Fourier transform infrared spectra (FT-IR). The resulting copolymers were temperature-sensitive and the lower critical solution temperature (LCST) was affected by their compositions. The graft copolymers obtained in this study exhibited low critical micelle formation concentration (CMC) values that were affected by the content of PLLA. Spherical nanoparticles with degradable cores were prepared from aqueous solutions of the amphiphilic graft polymers by a dialysis method. Dynamic light scattering (DLS) results indicated that the particle size increased with increase of PLLA content in the copolymer. The morphologies of prepared nanoparticles were observed by transmission electron microscopy (TEM). The prepared PNDH- g-PLLA nanoparticles with thermosensitive and biodegradable properties may have practical application in drug delivery and controlled drug release.

Synthesis of a graft polymer PVAc-g-[P(AN-r-BVE)-b-PCHO] in “one-step” by radical/cationic transformation polymerization and coupling reaction

This article reports a new ‘‘one-step’’ synthesis of graft polymers based on the radical/cationic transformation polymerization. Using the synthetic method proposed, a graft polymer (PVAc-g-[P(AN-r-BVE)b-PCHO]) consisting of a partly hydrolyzed poly(vinyl acetate) (PVAc-OH) backbone and block polymer grafts of acrylonitrile/n-butyl vinyl ether random copolymer (P(AN-r-BVE)) and poly(cyclohexene oxide) (PCHO) was synthesized in situ by radical/cationic transformation polymerization of a mixture of AN/ BVE/CHO in the presence of PVAc-OH. The graft polymer, PVAc-g-[P(AN-r-BVE)-b-PCHO], was fully characterized by 1 H NMR, IR, gel permeation chromatography and differential scanning calorimetry. The graft polymer, PVAc-g-[P(AN-r-BVE)-b-PCHO], was hydrolyzed with NaOH to form a poly(vinyl alcohol)based amphiphilic graft polymer, PVA-g-[P(AN-r-BVE)-b-PCHO]. The aggregation behavior of the amphiphilic graft polymer was investigated briefly by atomic force microscopy and dynamic light scattering measurements.

Thermoplastic amphiphilic conetworks

Our main objective was the design, synthesis, characterization, and testing of a novel class of materials, thermoplastic amphiphilic conetworks (TP-APCNs). A further objective was the evaluation of TP-APCNs as biomaterials, for example, as immunoisolatory membranes in a bioartificial pancreas, or as extended-wear soft contact lenses. The synthesis of the first TP-APCNs was accomplished by blending an amphiphilic graft polymer, poly(dimethyl acryl amide)-g-polydimethylsiloxane (PDMAAm-g-PDMS), with a commercial PDMS-containing polyurethane (PU). The common PDMS segments coalesce and form a single phase, whereas the hard/crystalline segments of the PU physically crosslink the blend. The properties of TP-APCNs can be controlled by the graft/PU ratio and segment molecular weights. TP-APCNs with cocontinuous hydrophilic and hydrophobic phases were prepared as demonstrated by swelling in water and n-heptane. Depending on the blend ratio and molecular weights, optically clear water-swollen TP-APCNs with 0.5–4 MPa tensile strength, 70–280% elongation, together with 2–11 × 10−7 cm2/s glucose permeability, and 1.2–8 × 10−8 cm2/s insulin permeability were prepared. TP-APCNs are processible by casting and molding. © 2008 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 47: 682–691, 2009

Pentalysine-Grafted ROMP Polymers for DNA Complexation and Delivery

Amphiphilic graft polymers, containing oligolysine groups pendent to a hydrophobic polycyclooctene backbone, were used to form polyplexes with plasmid DNA pZsGreen1-N1. These poly(cyclooctene- graft-pentalysine) structures were found to be effective transfection reagents for COS-1 and HeLa cells. In the case of polymer 1e (average degree of polymerization of 206), protein expression levels 48 h post-transfection were found to be comparable to, or better than, commercial transfection reagents jetPEI and SuperFect. With HeLa cells, GFP expression levels were better than Lipofectamine 2000. Of particular interest was the excellent cell viability seen in experiments with polyplexes formed from the pentalysine-grafted polymers. In the example of the highest molecular weight graft copolymer, polymer 1e, cell viability relative to untreated cells was 99% with COS-1 cells and 92% with HeLa cells in contrast to the commercial reagents, which gave 67-80% with COS-1 cells and 17-52% with HeLa cells. The effectiveness of these polyolefin- graft-pentalysine structures as DNA delivery vehicles is attributed to their amphiphilic nature and branched architecture.

Self-assembled polyethylenimine-graft-poly(ε-caprolactone) micelles as potential dual carriers of genes and anticancer drugs

A series of amphiphilic cationic graft polymers (PEC) were synthesized by coupling poly(ε-caprolactone) of differing molecular weights (MW) to low MW branched polyethylenimine via an amide group. IR, 1H-NMR and GPC were employed to characterize the graft copolymers. The self-assembly characteristics of these copolymers in an aqueous solution were studied by fluorescence techniques. The critical micelle concentration (CMC) varied from 0.044 to 0.032g/L when the MW of poly(ε-caprolactone) increased from 1800 to 5500. The micelles formed electrostatic complexes with a reporter gene (pCMV-Luc) after an anticancer drug, Doxorubicin (DOX), was loaded by dialysis method. Gel retardation studies proved that micelles with or without DOX were able to complex with DNA completely at an equivalent N/P ratio of around 2.0, indicating that drug loading did not interfere in the interaction between the PEI shell and DNA. Particle size slightly decreased at higher N/P ratios of polyplexes, but increased with drug encapsulation. It was also noted that DNA/micelle complexes were significantly less toxic to HepG2 cells than blank PEC micelles, and improved gene transfection efficiency (about 3 orders of magnitude greater than PEI 25K alone at most) whether DOX was present in the system or not. These results suggest that this group of cationic graft polymers may be a potential candidate for the development of a drug delivery system that can examine the synergistic effects of combined drug and gene therapy.

Amphiphilic copolymer micelles containing PEG with sulfonate end-group

A PEG macromer with methacryloyl and sulfonate group at the end of each chain was prepared and used for the radical copolymerization with butyl or PPG methacrylate. The resulting amphiphilic graft polymers were soluble in water and methanol, and dynamic light scattering measurements suggested the formation of nano-sized micelles in the aqueous medium.

Bioadhesion of Polyion Complex (PlC) Hydrogels Composed of Amphiphilic Phospholipid Polymers

To investigate the tissue adhesive function of a hydrogel composed of biocompatible amphiphilic polymers, random and graft polymers were prepared from 2-methacryloyloxyethyl phosphorylcholine (MPC), electrolyte monomers and hydrophobic n-butyl methacrylate (BMA). The results of the fluorescence study suggested enhanced electrostatic interaction in the graft polymers compared to the random polymers. This is due to the strategically designed architectures and the hydrophobic BMA units. The results of the cytotoxicity test showed that the cytotoxicity of the MPC polymers was lower than that of glutaraldehyde, which is a crosslinking agent in the aldehyde-type tissue adhesives and is known to cause serious side effects. The cationic MPC polymers demonstrated higher cytotoxicity compared to the anionic ones, which demonstrated no significant cytotoxicity. The tissue adhesion of the PlC hydrogels was lower than that of a commercially available fibrin glue. However, the tissue adhesive strength increased with an increase in the polymer concentration and could be controlled by the water content of the hydrogel. In addition, balance of the electrolyte units for the PIC formation and the tissue adhesion is crucial for expression of adhesion. Although further investigation of the biocompatibility is required, it can be concluded that the PlC hydrogels formed by the amphiphilic MPC polymers can be a promising tissue adhesive which demonstrate tissue adhesion and biocompatibility according to the architectures and chemical structures.

Synthesis and characterization of poly-α,β-[N-(2-hydroxyethyl)-L-aspartamide]-g-poly(glycolide) amphiphilic graft copolymers as potential drug carriers

A series of biodegradable amphiphilic graft polymers were successfully synthesized by grafting poly(glycolide) (PGA) sequences onto a water-soluble poly-α,β-[N-(2-hydroxyethyl)-L-aspartamide] (PHEA) backbone. These novel graft polymers were synthesized by the ring-opening polymerization initiated by the macroinitiator PHEA bearing hydroxyl groups without adding any catalyst. The graft polymers were characterized by Fourier transform infrared spectroscopy (FTIR), 1H nuclear magnetic resonance spectroscopy (1H NMR), combined size-exclusion chromatography (SEC) and multiangle laser light scattering (MALLS) analysis, and differential scanning calorimetry (DSC). By controlling the feed ratio of the macroinitiator to the monomer, graft polymers with different branch lengths can be obtained. The degradation behaviors of the copolymers were studied. Based on the amphiphilicity of the graft copolymers, nanoparticle drug delivery systems were prepared by the direct dissolution method and the dialysis method, and the in vitro drug release behavior was investigated. Transmission electron microscopy (TEM) images demonstrated that these nanoparticles were regularly spherical in shape. The particle size and distribution of the nanoparticles were measured.

Poly-α,β-(N-(2-hydroxyethyl)-L-aspartamide)-g-poly(1,3-trimethylene carbonate) amphiphilic graft co-polymer as a potential drug carrier

A biodegradable amphiphilic graft polymer was successfully synthesized by grafting hydrophobic poly(1,3-trimethylene carbonate) (PTMC) sequences onto a hydrophilic poly-α,β-(N-(2-hydroxyethyl)-L-aspartamide) (PHEA) backbone. The graft polymer, PHEA-g-PTMC, was synthesized by ring-opening polymerization initiated by the macroinitiator PHEA bearing hydroxyl groups without adding any catalyst. The graft polymer was characterized by Fourier transform infrared spectroscopy, 1H-nuclear magnetic resonance spectroscopy, combined size-exclusion chromatography and multiangle laser light scattering analysis. Two drugs with distinct water solubility, prednisone acetate and tegafur, were encapsulated in the PHEA-g-PTMC nanoparticles. The in vitro release of two drugs from PHEA-g-PTMC nanoparticle drug-delivery systems was investigated.