Synthesis And In Vitro Drug Release Behavior Of Novel Biodegradable Polymeric Nanoparticles

The continuous development of new drug delivery systems is driven by the need to maximize therapeutic activity while minimizing negative side effects. In order to improve the specific delivery of drugs several drug carriers such as liposomes, microparticles, nano-associates, nanoparticle, drug polymer conjugates and polymeric micelles, have been developed. In recent years, amphiphilic block copolymers consisting of hydrophilic and hydrophobic segment have attracted much attention because of their unique phase behavior in aqueous media and potential applications as drug delivery systems.Core-shell type nanoparticles or polymeric micelles can be formed through self-assembly of amphiphilic copolymers in aqueous environments. Nanoparticles as drug carriers can solubilize poorly water-soluble drugs in their inner core, avoid being quickly taken up by the reticuloendothelial system (RES) and prolong circulation time in the blood. Drug-loaded nanoparticles can also passively target drugs to specific sites and reduce side effects. Due to good biocompatibility and hydrophilicity of poly (ethylene glycol) (PEG), AB or ABA block copolymers containing PEG as hydrophilic segment and biodegradable polyesters such as poly (ε-caprolactone) (PCL) or polylactide (PLA) as hydrophobic block have been widely studied.Although nano-sized drug carriers are investigated over the past decades, it's still difficult to obtain biocompatible, stable and narrow polydisperse polymeric nanoparticles. Chapter 1 presents a detailed review of the recent progress achieved in polymeric nanoparticles.Aliphatic polycarbonates, a class of biomedical polymers with good biocompatibility, biodegradability and mechanical property, have been widely used as surgical sutures, drug delivery vectors and tissue scaffolds. In chapter 2 and 3, two series of amphiphilic triblock copolymers with PEG as hydrophilic segment and poly(trimethylene carbonate) (PTMC) or poly(2,2-dimethyl trimethylene carbonate) (PDTC) as hydrophobic blocks were synthesized by ring-opening polymerization of TMC or DTC initiated by dihydroxyl PEG. The structure and properties of all thetriblock copolymers was characterized by FT-IR, *H NMR^ GPC and DSC. Novel polymeric micelles of triblock copolymers were prepared by dialysis technique. The properties of polymeric micelles were investigated by fluorescent spectroscopy and dynamic light scattering for the first time. The critical micelle concentration (CMC) was 35~92mg/L for PTMC-PEG-PTMC and 5~51mg/L for PDTC-PEG-PDTC, respectively. Under the same preparation condition, the CMC of PTMC-PEG-PTMC obtained was bigger than that of PDTC-PEG-PDTC, this is probably due to the increasing lypophilic character of the hydrophobic segment. Furthermore, micelle size of PTMC-PEG-PTMC (50~160nm) was smaller than that of PDTC-PEG-PDTC (80~280nm). In vitro drug controlled release behavior of all polymeric nanoparticles was also investigated. Anticancer drugs MTX and 5-Fu as model drugs were encapsulated into the polymeric nanoparticles. After the initial burst release, anticancer drugs were continuously released from these nanoparticles. Release rate increased as increasing Mw or content of PEG segment incorporated in triblock copolymers.In addition to amphiphilic triblock copolymers, amphiphilic diblock copolymers can also form polymeric micelles in aqueous environments with different dynamic model. In chapter 4, four amphiphilic diblock copolymers MePEG-PDLLA were synthesized and evaluated as drug carriers. Polymeric micelles were prepared by the dialysis method with the mean diameters of 50~200nm. TEM image demonstrated that MePEG-PDLLA nanoparticles were regularly spherical in shape. X-ray diffraction demonstrated that anticancer drug MTX was molecularly dispersed in the polymeric nanoparticles. In vitro drug release behavior indicated that there was slightly burst effect in the initial period, and then MTX was continuously released from polymeric nanoparticles. Less than 50% MTX was released in 10 days. Release rate decreased as increasing length of hydrophobic PDLLA segment and drug loading content.The kinetics of drug release from polymeric nanoparticles was complicated. So a thorough exploration of relationship between physicochemical characteristics of polymer and release behavior will be very helpful to design more efficient drug delivery systems. In chapter 5, poly(e-caprolactone) was chosen as hydrophobic block and a series of triblock copolymers were synthesized. Hydrophilic PEG segment with different molecular weight or molar ratios were used to modulate the properties of PCL-PEG-PCL triblock copolymers. Polymeric micelle in aqueous solution was investigated by fluorescence spectroscopy and dynamic light scattering. Polymericmicelles were obtained with the mean diameters of 30~280nm. The morphology of PCL-PEG-PCL nanoparticles was observed by TEM. X-ray diffraction demonstrated that anticancer drug 5-Fu was molecularly dispersed in the polymeric nanoparticles. PCL has good drug permeability and in vitro drug release behavior indicated that there was slightly burst effect in the initial period, and then 5-Fu was continuously released from polymeric nanoparticles. Release rate increased as increasing Mw and content of PEG segment incorporated in triblock copolymers.Conventional amphiphilic di- or tri- block copolymers are synthesized by ring-opening polymerization of lactide or lactones initiated by hydroxyl groups of PEG In chapter 6, novel PEG-PCL-PEG (BAB type) amphiphilic triblock copolymers were synthesized by coupling reaction with LDI as the chain extender. Core-shell type nanoparticles were prepared by nanoprecipitation method. Poorly water-soluble anticancer drug DMEP was easily encapsulated into polymeric nanoparticles due to hydrophobic interaction. In conventional PCL-PEG-PCL or mPEG-PCL system, I00~200nm or even bigger size was obtained because of the formation of intermicellar aggregation. In this case, all polymeric micelles were sublOOnm without aggregations. TEM image also demonstrated that. In vitro drug release behavior was investigated. DMEP was continuously released from polymeric nanoparticles. Drug release rate increased as increasing the length of PEG block. On the other hand, release rate decreased as increasing drug loading content.