Preparation Of Polymeric Drug Delivery Systems And Their Anticancer Efficacy Study

Nanoparticles used as drug delivery systems are generally spherical particles which have the size between 1?1000 nm in diameter, and consist of different biodegradable materials such as natural or synthetic polymers. The drugs or biological molecules are dissolved, entrapped, encapsulated or attached to the matrix of the polymer. The drug delivery systems have significant advantages over free drugs, such as prolonging the circulation in the bloodstream, reducing the deposit of formulation, improving the solubility of hydrophobic drugs and reinforcing the surface of biological adhesion. Drug delivery therapeutics could enhance the concentration for enhanced diffusion to the diseased cells and minimize the side effects of drugs.Currently, the drug delivery systems are mainly divided into the natural polymer nanoparticles, the micelles based on amphiphilic block copolymers and the self-assembly of hydrophobically modified natural polymer. Non-covalent interactions, such as electrostatic and hydrogen bonding interactions, can also be used to impart amphiphilic character to biopolymers and fabricate nanoparticles, whereas, especially in ionic acidic and basic environments. The micelles based on block copolymers and the hydrophobically modified polysaccharides are frequently dissociated after systemic injection due to the blood flow dilution and fluid shear stress. Consequently, the drug trapped in the micelles will be released prematurely before reaching the lesion site. Therefore, the physical stability of the drug-loaded polymeric micelles becomes one of the most crucial factors influencing their therapeutic activity. In this dissertation, the dextran-poly(3-acrylamidophenylboronic acid) (Dextran-PAPBA) nanoparticles were prepared via a boronic acid-diol reaction and doxorubicin was loaded in the nanoparticles through electrostatic interaction. Star-shaped amphiphilic copolymers with a porphyrin core were also synthesized, and the paclitaxel (PTX) loaded micelles were prepared by the nano-precipitation. This dissertation is involved in the research on following three aspects:(1) Dextran-PAPBA nanoparticles were synthesized by a radical polymerization of the monomer APBA bound by dextran via a boronic acid-diol reaction in aqueous solution. No organic solvents and surfactants are needed during the preparation, and the size and composition of nanoparticles can be tuned by varying the feeding ratio of dextran to monomer. The obtained boron-rich nanoparticles have great application potential in boron neutron capture therapy for cancer treatment, since they may overcome the inherent drawbacks of small molecular boron neutron capture therapy, for example poor cellular uptake. Furthermore, the boronate ester binding can offer the nanoparticles improved stability and smaller size compared to non-covalent interaction.(2) Doxorubicin (DOX) was encapsulated in the Dextran-PAPBA nanoparticles through electrostatic interaction. The DOX loaded nanoparticles had a spherical shape, and exhibited a sustained and strongly pH-dependent release profile that favors the in vivo drug delivery performance of the nanoparticles. In vitro cytotoxicity tests revealed that the DOX released by the nanoparticles retains its pharmacological activity. In vivo real-time fluorescent imaging revealed that the DOX loaded nanoparticles could accumulate in the liver tissue of the tumor bearing mice. The biodistribution of DOX in tissues consisted well with the results of the noninvasive and real time imaging. In vivo antitumor activity and histology studies indicated that the nanoparticles formulation was superior in anticancer effect to free DOX on orthotopic implanted murine hepatic H22 tumor-bearing mice model.(3) Star-shaped poly(?-caprolactone)-b-poly(ethylene oxide) amphiphilic copolymers with a tetrakis-(4-aminophenyl)-terminated porphyrin core were synthesized, and the drug-loaded micelles were prepared by the self-assembly of this star amphiphilic copolymer and in situ encapsulation of PTX. The PTX loaded micelles had a spherical shape about 38±15 nm, and exhibited a sustained release profile. In vitro cytotoxicity tests revealed that the PTX released from the micelles remains its pharmacological activity and showed a slightly higher cytotoxicity than Taxol(?). In virtue of the inherent fluorescent characteristic of the porphyrin moiety, the cellular uptake and biodistribution of the PTX-loaded micelles can be easily monitored by fluorescent imaging. The in vivo real-time fluorescent imaging revealed that the drug-loaded micelles could accumulate at tumor site via the blood circulation in tumor-bearing mice. In vivo antitumor efficacy examination exhibited significantly superior antitumor effect compared to the Taxol(?) and low toxicity to the living mice.