Synthesis And Bio-Applications Of PH-responsive Hyperbranched Polymers

Nowadays, hyperbranched polymers have attracted great attention in the field of biology, especially for the stimuli-responsive polymers with different topologies. In this dissertation, a series of pH-responsive hyperbranched polymers have been successfully synthesized via atom transfer radical polymerization. First, we prepared drug-loading unimicelles formed by pH-responsive hyperbranched polymers and studied their applications in drug delivery system. Also, we prepared pH-responsive hyperbranched polymers which can converse charge after degradation and studied their applications as gene delivery vectors. Primary results are as follows:1. Anticancer drug camptothecin (CPT)-loaded hyperbranched star copolymers, H(PHPMA-co-PMACPT-co-PBS2MOE)(POEGMA)ns have been successfully prepared by two steps of atom transfer radical polymerization (ATRP). The first step is polymerization of2-hydroxypropyl methacrylate (HPMA), methacryloyloxy-3-thiahexanoyl-CPT (MACPT) and2-(2’-bromoisobutyryloxy) ethyl2"-methacryloyloxyethyl disulfide (BS2MOE), and the resultant hyperbranched polymer H(PHPMA-co-PMACPT-co-PBS2MOE) was used as macroinitiator in the subsequent ATRP of oligo(ethylene glycol) methacrylate (OEGMA). In the MACPT, the polymerizable methacrylate unit and CPT are linked by an acid-labile β-thiopropionate linkage, thus, the H(PHPMA-co-PMACPT-co-PBS2MOE)(POEGMA)ns are pH-responsive. When the hyperbranched star copolymers are dissolved in water, unimolecular micelles with the H(PHPMA-co-PMACPT-co-PBS2MOE) as core and the POEGMA as shell are formed. The controlled release of CPT from the unimolecular micelles can be triggered by mild acidic pH (5.0), and the amount of CPT released in a solution of pH=5.0is higher than that in a solution of pH=7.4. Cell uptake experiments show that the unimolecular micelles could be internalized by HepG2cells. The micelles display higher cytotoxicity in an aqueous solution of pH=5.0than that in the neutral solution (pH=7.4). The hyperbranched star copolymers containing disulfide linkage can be degraded under reducing agent, such as glutathione and dithiothreitol (DTT). Such system with stimuli-responsive drug release properties provide a new strategy for design of drug carriers and may have potential applications in clinical use.2. pH-responsive hyperbranched star copolymers H(PDMAESP-co-PBS2MOE)(POEGMA)ns have been successfully prepared by two steps of atom transfer radical polymerization (ATRP). The first step is polymerization of methacryloyloxy-3-thiahexanoyl-N’N"-dimethyl acetate (DMAESP) and2-(2’-bromoisobutyryloxy) ethyl2"-methacryloyl oxyethyl disulfide (BS2MOE) and the resultant H(PDMAESP-CO-PBS2MOE) was used as macroinitiator in the subsequent ATRP of oligo (ethylene glycol) methacrylate (OEGMA). In DMAESP, the methacrylate unit and tertiary amines are linked by an acid-labile β-thiopropionate linkage, which can be slowly degraded under mild acidic conditions (pH=5.0) to form carboxyl terminals, and the H(PDMAESP-co-PBS2MOE)(POEGMA)ns are pH-responsive. Besides, hyperbranched star copolymers containing disulfide bonds can be degraded in the presence of glutathione in cells, thus, the polymers are also redox-responsive. When the hyperbranched star copolymers are self-assembled, micelles with the H(PHPMA-co-PMACPT-co-PBS2MOE) as core and the POEGMA as shell are formed and the micelles can load DNA. Therefore, such polymers can be used as vectors in gene delivery system.