Preparation Of Stimuli-responsive Amphiphilic Block Copolymers Micelles For Controlled Drug Delivery

Amphiphilic block copolymers were a kind of special polymer which produced by joining two or more chemically distinct polymer blocks. The amphiphilic block copolymers, due to its particularity and variety of the structures, could be self-assembled into diverse ordered nanostructured materials in selective solution. These resultant polymer aggregates have great potential applications in many areas, such as tissue engineering, drug delivery systems, chemical and biological sensors. In recent years, the applied value of stimuli-responsive block copolymers has received extensive attention in biomedical science especially in drug controlled release system. Some special functional groups can be incorporated into amphiphilic block copolymers to prepare stimuli-responsive amphiphilic block copolymers. These functional groups could respond to external stimuli such as pH, light, temperature and ionic strength. In this study, we synthesized series of well-defined stimuli-responsive polymers through reversible addition-fragmentation chain transfer (RAFT) polymerization, and investigated the self-assembly behavior of the supramolecular copolymers. The properties and structures, especially the response behavior to the external stimuli, of the obtained copolymers were systematically characterized. The structure-property relationships and potential applications of stimuli-responsive block copolymers in smart drug delivery systems were also investigated.1. In this part, a novel fluorescent amphiphilic pH-responsive block copolymer (PSMA-b-P(St-co-VK)) was prepared by RAFT polymerization. The block copolymer was subsequently characterized by FT-IR spectroscopy,1H NMR spectroscopy, and GPC. The copolymer could self-assemble into pH-responsive core-shell micelle with the hydrophobic P(St-co-VK) block as core, the pH-sensitive PSMA block as shell in aqueous media. The critical micelle concentration values were about 0.79 mg/L. TEM and DLS measurements indicated that the micelles were regularly spherical in shape with an average diameter of about 85 nm and narrow distribution in aqueous media. An interesting pH-dependent size of the micelles was observed by DLS and scanning electron microscopy (SEM). Under acidic conditions, the diameter of the micelles decreased with the increasing of pH values, however the diameter size of the polymer micelles increases with the increase of the pH under alkaline environment. The drug delivery behaviors of the DOX-loaded micelles at physiological conditions were studied, and the DOX-loaded micelles showed a remarkable pH-responsive drug release behavior. MTTassay was used to evaluate cytotoxicity of the polymeric micelles. The in vitro antitumor activity were evaluated in human breast carcinoma cell line MCF-7 and murine colon carcinoma cell line CT-26 by use of the nanosized micelles as the carrier of the Doxorubicin (DOX). The results showed that the amphiphilicblock copolymer PSMA-b-P(St-co-VK) with good biocompatibility was one of novel and ideal biomaterials as DOX nano-carrier. The polymer micelles and DOX-loaded micelles are both fluorescent, so the fluorescent and pH-responsive polymeric micelles are expected to be a potential labeling material for biological fluorescence imaging.2. A novel pH-sensitive amphiphilic block copolymer poly (isobutyl acrylate-co-crylic acid)-b-poly(2-hydroxypropyl acrylate) (P(IBA-co-AA)-b-PHPA), which composed of poly(isobutyl acrylate-co-crylic acid) random copolymer block and poly (hydroxypropyl acrylate), was synthesized by RAFT polymerization. The block copolymer was characterized by FT-IR,1H NMR, and GPC. Nanosized micelles were formed by self-assembly method when the P(IBA-co-AA)-b-PHPA was dissolved in water solution. The critical micelle concentration value was about 2.0 mg/L. These nanosized micelles were characterized by TEM and DLS. The assembled micelles were regularly spherical in the shape with an average diameter of about 100 nm. By DLS and SEM, we found that the diameter of the micelles increased with increasing the pH values. The drug delivery behaviors of the micelles embedding anti-cancer drug paclitexel (PTX) in a simulated human body environment were studied. The Cell Counting Kit-8 assay (CCK-8) was used to evaluate cytotoxicity of the polymeric micelles. The in vitro antitumor activity was evaluated in human breast carcinoma cell line MCF-7 and human lung adenocarcinoma cell line A-549. The results also showed that P(IBA-co-AA)-b-PHPA micelles exhibited pH-sensitive behavior because of the presence of AA. The amphiphilicblock copolymer P(IBA-co-AA)-b-PHPA, as one of novel and ideal biomaterials, was a promising anti-cancer drug carrier.3. Poly(styrene-co-maleic anhydride)-b-poly(single-methoxypoly(ethylene glycol) methyl acrylate) (PSMA-b-PMAPEG) was synthesized by RAFT polymerization and further modified by p-aminoazobenzene to form photo-responsive block copolymer P(St-alt-Ma/azo-MaIM)-b-PMAPEG. The copolymer was characterized by FT-IR,1H NMR, and GPC. Nanosized micelles were formed through the self-assembly of P(St-alt-Ma/azo-MaIM)-b-PMAPEG in water solution. TEM and DLS measurements showed that the micelles were regularly spherical in shape with an average diameter of about 100 nm. The critical micelle concentration values of the self-assembled micelles were 2.1 mg/L by fluorescent probe technique at pH 7.4. The photo-responsive behavior of the copolymer micelles was studied by UV-Vis spectroscopy, DLS and Scanning electrom microscopy (SEM). These results indicate that the size change of the copolymer micelles under the irradiation with different wavelength was caused by the isomerization of azobenzene which changed from trans-form to cis-form by UV irradiation of 365 nm and recovered to trans-form by visible light irradiation of 420 nm.