Functional Biodegradable Polycarbonates: Design And Synthesis

Biodegradable aliphatic polycarbonates are one of the most important biomedical materials. Aliphatic polycarbonates are usually degraded via surface erosion mechanism to neutral diols and carbon dioxide. Biodegradable polycarbonates have good biocompatibility and physico-mechanical properties. The physical, chemical and biological properties of polycarbonates may further be tuned by changing their main chain strutures and incorporating functional pendent groups. The first chapter of this thesis gives a general introduction to biodegradable aliphatic polycarbonates including their structures, syntheses and applications.The second chapter describes rapidly pH-responsive biodegradable micelles based on block copolymers of a novel acid-labile polycarbonate hydrophobe and poly(ethylene glycol) (PEG). Two new cyclic aliphatic carbonate monomers, mono-2,4,6-trimethoxybenzylidene-pentaerythritol carbonate (TMBPEC, 2a) and mono-4-methoxybenzylidene-pentaerythritol carbonate (MBPEC, 2b) were designed and successfully synthesized via a two-step procedure. The ring-opening polymerization of 2a or 2b in the presence of methoxy PEG in dichloromethane at 50°C using zinc bis[bis(trimethylsilyl)amide] as a catalyst yielded the corresponding block copolymers PEG-PTMBPEC (3a) or PEG-PMBPEC (3b) with low polydispersities (PDI 1.03-1.04). These block copolymers readily formed micelles in water with sizes of about 150 nm as determined by dynamic light scattering (DLS). The hydrolysis of the acetals of the polycarbonate showed that the acetals of micelles 3a while stable at pH7.4 are prone to rapid hydrolysis at mildly acidic pH of 4.0 and 5.0, with a half life of 1 and 6.5 hrs, respectively. Both paclitaxel and doxorubicin could be efficiently encapsulated into micelles 3a achieving high drug loading content (13.0 wt.% and 11.7 wt.%, respectively). The in vitro release studies showed clearly a pH dependent release behavior.The third chapter reports pH-sensitive degradable polymersomes based on PEG-PTMBPEC copolymer for triggered released of hydrophilic and hydrophobic anti-cancer drugs. DLS showed that polymersomes of PEG1.9k-PTMBPEC6k had average sizes of 100~200 nm. The acetals of polymersomes, similar to those of PEG5k-PTMBPEC5.8k micelles, though stable at pH7.4 were prone to fast hydrolysis at mildly acidic pH of 4.0 and 5.0, with half lives of 0.5 and 3 d, respectively. Drug encapsulation studies revealed that polymersomes were able to simultaneously load paclitaxel (61.4-65.2%) and doxorubicin hydrochloride (30.0-37.7%), whereas micelles loaded PTX only. The in vitro release studies demonstrated that release of PTX and DOX HCl from polymersomes was highly pH-dependent. Furthermore, much higher release rates were observed for PTX release from the polymersomes compared to that from the micelles under otherwise the same conditions.The fourth chapter describes versatile synthesis of functional biodegradable polymers from novel cyclic carbonate monomers, acryloyl carbonate (AC) and methacryloyl carbonate (MAC), by combining ring-opening polymerization (ROP) and Michael addition chemistry. AC and MAC monomers were synthesized in four straightforward steps with good overall yields (ca. 40%). AC and MAC were able to copolymerize withε-caprolactone (ε-CL) and D,L-lactide (LA) in toluene at 110°C using stannous octoate as a catalyst, yielding biodegradable copolymers with controlled acryloyl functional groups and molecular weights. The acryloyl groups were amenable to the Michael addition conjugate reaction with varying thiol-containing molecules such as 2-mercaptoethanol, 3-mercaptopropanoic acid, cysteamine, cysteine, and arginine-glycine-aspartic acid-cysteine (RGDC) peptide under mild conditions. Notably, 100% functionalization was achieved with 2-mercaptoethanol, cysteamine and cysteine. Initial cell culture studies demonstrated enhanced cell adhesion and growth on films containing functional RGDC peptides as compared to those of the parent copolymer as well as tissue culture plastic.