Controlled Synthesis Of Stimuli-responsive Glycopolymers And Study As Drug Carriers

Local microenvironment changes of organisms (eg., pH, temperature, and glucose concentration) are closely related to the pathological process of many important diseases. For example, the cell metabolism of tumor lesions is active, which causes local pH to decrease and temperature to increase; the continuous rise of blood glucose levels leads to diabetes and its complication. Therefore, the effective monitoring of biological microenvironment changes is very important for diagnosis and treatment of related diseases. According to the physiological and pathological feature of disease microenvironment, the stimuli-responsive carriers can be designed. These carriers may achieve controlled release of the drug, increase drug effectiveness, and reduce drug’s side effects. In addition, sugar plays identified, mediated and regulated roles in the process of life activities (eg., cell differentiation, development, aging, cancer, information transmission) and seriouse diseases. Glycopolymer not only maintain the sepcical nature of the sugar, but also exceed the function of natural sugar, and greatly expand its application. Thus, glycopolymers have been widely used in drug delivery. Based on the above fact, we prepared well-defined glycopolyers via atom transfer radical polymerization (ATRP). The glycopolymers can self-assemble to form stimuli-responsive nanocarriers for drug delivery.1. Fabrication of pH-and glucose-sensitive glycopolymer nanoparticlesAmphiphilic poly(acrylic acid-co-acrylamidophenylboronic acid)-block-poly(2-acryloxyethyl galactose)-block-poly(acrylic acid-co-acrylamidophenylboronic acid)(((PAA-co-PAAPBA)-b-)2PAEG) glycopolymer was fabricated:The poly(2-acryloyloxyethyl pentaacetylgalactoside)(PAEAcG) with narrow molecular weight distributions (MW/Mn≤1.22) was prepared by ATRP using dibromo-p-xylene as initiator. Then the well-defined triblock copolymer poly(t-butyl acrylate)-b-poly(2-acryloyloxyethyl pentaacetylgalactoside)-b-poly(t-butyl acrylate)(PtBA-b-PAEAcG-b-PtBA) was synthesized by ATRP of t-butyl acrylate using PAEAcG homopolymer with dibromo end groups as macroinitiator. After hydrolysis of t-butyl acrylate block, amide linkage and deacetylation, the final glycopolymer ((PAA-co-PAAPBA)-b-)2PAEG11was obtained. Amphiphilic ((PAA-co-PAAPBA)-b-)2PAEG11can self-assemble to form nanoparticles in aqueous solution. The size of the nanoparticles was about250nm. The nanoparticles showed the pH-and glucose-responsitivity. Insulin was encapsulated into the nanoparticles, the loading capacity was about20%. The in vitro release profiles of insulin-loaded nanoparticles depended on pH values and glucose concentration of solution. Furthermore, the glycopolymer nanoparticles had good cytocompatibility.2. Phenylboronic acid functionalized glycopolymer nanoparticles for transmucosal insulin deliveryBased on the first part,((PAA-co-PAAPBA)-b-)2PAEG26nanoparticles were used as transmucosal insulin delivery carriers. The nanoparticles showed the strong inhibitory activity toward leucine aminopeptidase which is present on nasal mucosa. Thenanoparticles therefore show promise for protecting insulin from degradation of enzyme in nasal cavity. The nanoparticles presented high mucin adsorption ability. The amount of mucin adsorbed by the nanoparticles reached150μg (per2mg nanoparticles). The nanoparticles could increase the contact time of the insulin with nasal cavity. The nanoparticles could internalize into Caco-2cells via receptor-mediated recognition and overcome mucosal barriers, thereby acting as a true drug carrier for transmucosal delivery. After nasal administration, the nanoparticles could significantly enhance the pharmacological availability of insulin. Because of the sustained insulin release, the insulin-loaded nanoparticles showed prolonged hypoglycemic action. Additionally, the nanoparticles did not cause inflammation to nasal mucosa tissues. Thus, this study advances the nanoparticles as novel drug delivery systems for transnasal delivery of insulin.3. Reducible glycopolymer micelles for hepatocytes-targeting delivery of DOXA novel galactose-decorated cross-linked micelles with ionic cores using cystamine as a biodegradable cross-linker was prepared by using block ionomer complexes of poly(ethylene glycol)-b-poly(2-acryloxyethyl-galactose)-b-poly(acrylic acid)(PEG-b-PAEG-b-PAA) and Ca2+. Doxorubicin (DOX) was successfully incorporated into the ionic cores of such micelles via electrostatic interactions. The micelles were spherical in shape, with an average size of100nm. The in vitro release studies confirmed that the DOX-loaded micelles accomplished rapid drug release under reducing condition. The micelles efficiently delivered and released DOX into the cell nucleus of HepG2cells. Thus, strong fluorescence was observed in HepG cells. In contrast, little fluorescence was observed in NIH3T3cells after incubation with the DOX-loaded micelles. Interestingly, the DOX-loaded micelles retained higher cell inhibition efficiency in HepG2cells as compared with NIH3T3cells. These results indicate that the micelles have great potential in liver tumor chemotherapy.