Study On Modification Of PLA And Biomedical Applications Of Modified PLA

Polylactide (PLA), one of the most important synthetic biodegradable materials in biomedical application, has been widely used as carriers in drug delivery, sutures and temporary matrixes or scaffolds in tissue engineering due to its biodegradability, good biocompatibility, high mechanical properties and excellent shaping and molding properties. However, some factors limit its applications:polylactide (PLA, for short) does not contain any reactive groups, so it is difficulty in their modification; another is low hydrophilicity. In this thesis, aliphatic carbonic ester was introduced on PLA firstly to obtain polymer of LA and carbonic ester (P(LA-co-CA), for short). The biocompatibility, physical-chemical properties and biodegradability were adjusted. Some polymers based on P(LA-co-CA) were synthetized to be used as drug carrier for controlling drug release, targeting to tumor cells via RGD receptor and fluorescence imaging. As well as used as drug carrier, P(LA-co-CA) can be used as bone repair materials. P(LA-co-CA) grafted on modified hydroxyapatite (HA, for short) to produce HA-P(LA-co-CA), then HA-P(LA-co-CA) and PLGA were mixed to composite materials used as bone repair materials. The main innovative works of this dissertation are as follows:1. The copolymer of P(LA-co-CAB) was prepared using ring-opening polymerization with zinc diethy (ZnEt2) as catalyst, and then took off benzyl oxygen group to obtain P(LA-co-CA). Based on P(LA-co-CA), some polymers were synthetized, including amphiphilic copolymers P(LA-co-CA)-mPEG and PEG-P(LA-co-CA), and two functionalized graft copolymers, P(LA-co-CA)-PEG-RGD and P(LA-co-CA)-FITC.1H NMR, FT-IR and GPC were used to characterize polymers.2. Amphiphilic polymers were used as carriers, with docetaxel (DOC, in short) as a model drug to establish a nano drug delivery system. By optimizing the experimental conditions, the graft copolymer P(LA-co-CA)-mPEG was used as a carrier to prepare drug loaded nanoparticles. Morphology was characterized by scanning electron microscopy (SEM) and the size and size distribution were determined by dynamic light scattering (DLS). SEM images and DLS results revealed that the particles are spherical in shape and about100nm in size, which is suitable for intravenous injection and close to the typically required size under physiological conditions. The drug release result indicates that the nanoparticles exhibitied initial burst release and followed by a sustained release, cumulative drug release about70%after72h. The size and naterials make the nanoparticles low uptake by the reticuloendotnenai system (RES), protecting the incorporated drug from fast degradation,)lood clearance and elimination from the body, targeting to the tumor issue in a passive manner via the "enhanced permeation and retention EPR)" effect. In vitro viability of HeLa cells, the results showed that the polymer itself is non-cytotoxic, but the loaded drug samples can significantly increase the efficacy of docetaxel. Thus, nanoparticles of P (LA-co-CA)-mPEG could be useful as biodegradable, biocompatible, and cell-specific targetable nano-structured carriers for intracellular delivery of hydrophobic anticancer drugs.3. Polymer nanoparticles have shown great promise for applications such as cancer cell targeting, distribution imaging, and anticancer drug delivery. PH-sensitive nanoparticles for such applications were prepared from the copolymer, poly(2-amino,1,3-propanediol carbonic ester-co-lactide)(P(LA-co-CA)), as well as a graft copolymer,(2-amino,1,3-propanediol carbonic ester-co-L-lactide)-g-methoxy-poly (ethylene glycol)(P(LA-co-CA)-mPEG) and two functionalized graft copolymers, P(LA-co-CA)-PEG-RGD and P(LA-co-CA)-FITC. The anticancer drug, docetaxel, was incorporated into the inner core of these multifunctional nanoparticles by dialysis. The morphology of the nanoparticles was characterized by high resolution transmission electron microscopy(TEM) and the size and size distribution were determined via dynamic light scattering (DLS). The particle size was found to be approximately110nanometers and release studies revealed that the drug released was faster in PBS at a pH5.0than at a pH of7.4. An MTT assay demonstrated that the materials of multifunctional nanoparticles were not cytotoxicity to human cervical cancer cells, and revealed that the targeting of the nanoparticles increased with an increasing amount of RGD.4. HCPT/PLGA nanoparticles have been prepared by using an anti-solvent precipitation method. The influences of different solvents and different concentrations of PLGA on nanoparticles, as well as drug loading capacity and entrapment efficienc, were investigated with water as anti-solvent. The release of HCPT/PLGA nanoparticles can be divided into two stages:an initial burst release in the first day and followed by a lag period. The cumulative release amount was only50%after28days.5. P(LA-co-CA) prepared in the previous stage was grafted to the surface of modified n-HA, then blend with the PLGA matrix to produced HA-P(LA-co-CA)/PLGA composite materials. The bone repair material was prepared with the melt-molding method. HA-P(LA-co-CA) grafting yield was analyzed through thermo gravimetric instrument (TGA), the internal structure and morphology were observed through scanning electron microscope (SEM), the tensile strength and bending strength of composite materials were tested by electronic universal material experiment machine. The results indicate that the grafting modification improved the hydrophilic performance and inhanced the interface strength between HA and PLGA, and increased the tensile strength and bending strength of composite material.