Synthesis, Self-assembly And Drug Release Of Novel Structural Polymers Based On Polymethacrylic Acid As A PH Sensitive Unit

Amphiphilic block copolymers or graft copolymers have found extensive application in bioscience, medicine and other fields due to their unique structure and properties, which has become a hot subject of researches. As a controlled release caririer, pH-responsive amphiphilic block copolymers can undergo phase transition with change in pH values of the environment, thus causing a pH-responsive drug release behavior. As a result, controlled and targeted drug delivery can be achieved. Despite the features, some problems still exist, such as low drug loading capacity and nonpersistent stability. Therefore, it is an urgent problem to be sovled in the study how to increase the loading capacity, to improve the stability of the micelles in blood circulation and to achieve the destination of better targeted drug delivery nowadays. Basaed on the above-mentioned description, two types of pH sensitive block copolymers were synthesized in this article. One was carbon nanotubes grafted with polymethylacrylic acid copolymers (CNTs-g-PMAA) with hydroxyl carbon nanotube as the hydrophobic segment and polymethylacrylic acid as hydrophilic segments, and the other was H-type block copolymer (modified carboxyl-terminated butadieneacrylonitrile and polymethylacrylic acid block copolymer) PMAA2-b-HTPBN-b-PMAA2 with HTPBN as hydrophobic segments and PMAA as hydrophilic segments. Their strutures were characterized and their self-assembly behevior in aqueous solution was studied. After that, the copolymers were applied in loading and drug release of hydrophobic anticancer drug, and biological properties were studied. The detail content is as follows:1. Synthesis of pH-responsive CNTs-g-PMAA copolymers and their self-assembly and drug release behavior. A series of CNTs-g-PMAA copolymers with different CNTs/PMAA ratios were synthesized by free radical chain transfer reaction using two methods. The structure was characterized through infrared spectroscopy (FT-IR) and nuclear magnetic resonance hydrogen spectrum technology (1H NMR). The polymers could self-assemble into nanoscaled micelles with special core-shell strcture. The critical micelle concentration (CMC) value, shape and size of the micelles were determined by surface tensiometer, transmission electron microscopy (TEM), dynamic light scattering laser granulometer (DLS), respectively. The micelles in different environments were observed as spherical structure, and the CMC values were within the scope of 120.33 to 251.19 mg/L. Zeta potential values were measured to be electronegative, and changed regularly in different pH value solutions. The UV-vis and DLS findings showed that the size of micelles changed with pH values, and phase transition point was at about pH=6.4, which showed pH-response. Cell toxicity measurement results showed that the micelles were non-toxic, so they can be applied as drug release carriers. The drug release behavior from the micelles carrying 10-hydroxy camptothecin (HCTP) was studied in simulated human body environments, and the results indicated that the release behavior was related to the environmental pH value. Therefore, CNTs-g-PMAA polymers can be potentially used as biomedical materials for drug loading and targeted release, especially for the increase in drug loadings.2. Synthesis, micellization and drug release of pH-responsive H-type amphiphilic block copolymer PMAA2-b-HTPBN-b-PMAA2. H-type block copolymer PMAA2-b-HTPBN-b-PMAA2, which consists of hydrophobic HTPBN segments and hydrophilic poly(methyl acrylic) segments hydrolyzed from poly(methyl acrylic acid tert-butyl ester), was synthesized by the method of atom transfer radical polymerization reaction. The structure was determined by FT-IR and 1H NMR, and the relative molecular mass was obtained through GPC. The copolymers self-assembled into spherical nanometer micelles with CMC values of 36.6-58.0 mg/L, zeta potential value from-24 to-34 mV. Dh measurements were obtained by DLS, which were consistent with the results measured by UV-vis. The conclusion suggested that the copolymers were pH-responsive. Compared with linear polymers with the same molecular weight, H-type polymer micelles had smaller particle size and CMC values, which showed that it owned better stability when circulating in the body. The cytotoxicity was determined by MTT method, and the results indicated that the toxicity of blank micelle and drug-loaded micelle was significantly lower than that of free drug. The in vitro drug release showed that a pH-dependent controlled drug release behavior could be obtained and release quantity was larger in lesions than in normal human body tissues. Therefore, the block polymers can be used for controlled drug release as a hydrophobic drug carrier.