Development Of Biodegradable Polymeric Microspheres As A Sustained-release System For Pulmonary Inhalation Treatment Against Lung Cancer

During the past several decades, the industry and technology fast development in However, the outdoor air pollution induced during the process is also severe and leading to an increasing amount of lung cancer sufferer. In numerous methods for the treatment of lung cancer, chemotherapy was regarded as the most effective treatment. In order to obtain the best therapeutic outcomes, the drugs were required to deposit in the lungs effectively and remain in situ as long as possible. For inhalation, the technique to form microparticles and the selected excipients ought to ensure appropriate aerosolization properties of the microparticles. Large porous microparticles were considered as the best selection to encapsulate drugs and deliver to the lungs. Firstly, various kinds of biodegradable microparticles were designed and their aerosolization property, drug control release ability and anti-cancer efficiency were investigated.After that, doxorubicin (DOX) loaded poly(lactic-co-glycolic acid) (PLGA) microparticles with internal pores (MP-D) were developed for long-acting release in pulmonary inhalation treatment. The PLGA microparticles exhibited favorable aerodynamic properties for pulmonary delivery. In vitro drug release profile suggested that MP-D have the advantage of long-term maintenance of drug concentrations. MTT assay demonstrated the in vitro anti-tumor efficiency of the DOX loaded PLGA microparticles. Furthermore, melanoma lung metastasis model was established to determine the in vivo anti-tumor efficiency. The mice treated with MP-D showed significantly fewer lesions than the untreated ones. The survival analysis indicated that MP-D prolonged the survival time of tumor-bearing mice. These results suggested that DOX loaded PLGA microparticles with internal pores have the potential to be used as long-acting release carriers in clinical lung cancer treatment.Finally, synergistic co-delivery of doxorubicin (DOX) and paclitaxel (PTX) encapsulated by PLGA porous microspheres were studied for in situ treatment of metastatic lung cancer. The synergistic effect of the combined drugs was investigated against B16F10 cells to obtain the optimal prescription for in vivo studies. The combination therapy showed great synergism when DOX was the majority in the combination therapy, while they showed moderate antagonism when PTX is in major. The combination of DOX and PTX at a molar ratio of 5/1 showed the best synergistic therapeutic effect in the free form. However, the drugs exhibited more synergism in the PLGA microspheres at a molar ratio of 2/1, due to the difference in drug release rate. The in vivo study verified the synergism of DOX and PTX at the optimal molar ratio. These results suggested that dual encapsulation of DOX and PTX in porous PLGA microspheres would be a promising technology for long effective lung cancer treatment.Besides, PEGylated poly(aspartate-g-OEI) copolymers were developed for in vivo gene transfer, named DAO and TAO. These copolymers exhibited favorable capacities in condensing plasmid DNA (pDNA) into nanosized particles (90-180 nm) with positive surface charges. Gene transfection efficiency of the copolymers (especially DAO) demonstrated improved performance compared to PE125k in both HeLa and HEK 293 cell lines in the presence of serum. Although MAO and DAO show similar gene transfection efficiency in vitro, DAO is shown to be more effective in vivo. The potential reason is that PEGylation enhance serum-resistance of the carriers and prolong gene transfection in vivo. For TAO, despite its PEG segment, the complex of copolymer/pDNA is encompassed by a cation shell and cannot reduce the serum effects. These results suggest that PEGylated diblock copolymers have potential as non-viral gene carriers in gene delivery systems for in vivo application.