Multifunctional Polymeric Drug Loaded Nanoparticles In Tumor Targeting Imaging And Therapy

Cancer is an important factor in hazards to human health. The effective method of cancerdiagnosis and treatment is a long-term dream in clinical oncology. With the development ofnanotechnology and its penetration to the field of medicine, drug-loaded nano-carriers haveopened up new avenue for tumor diagnosis and treatment. The aim of this thesis is developingmultifunctional vesicles for simultaneous targeting imaging, drug delivery and real timemonitoring of therapeutic effect.Firstly, we have modified the biocompatible polymer materials polyethylene glycol (PEG)and poly (lactic-co-glycolic) acid (PLGA) to amino or carboxyl terminated functionalpolymer. The superparamagnetic iron oxide (SPIO) nanoparticles with high magneticresponse were prepared. Then, three kinds of multi-functional drug-loaded nano-carriers werebuilt with the paclitaxel (PTX), docetaxel (Dtxl) and temozolomide (TMZ). The anti-tumorefficacy and MR imaging efficacy of the multi-functional drug-loaded nano-carriers wereassessed in tumor-bearing mice in vitro and in vivo. The molecular mechanism of tumor cellapoptosis induced by multi-functional nano-carriers was analysised by gene chip microarray.(1) Folate-targeted paclitaxel-loaded PLGA-PEG nanoparticlesFolate (FOL) mediated poly-lactide-co-glycolide-polyethylene glycol nanoparticles(FOL-PEG-PLGA NPs) bearing paclitaxel (PTX) were prepared for the effective delivery ofdrug to endometrial carcinoma. The average size, zeta potential and encapsulation efficiencyof FOL-targeted NPs were found to be around220nm,-30.43mV and95.6%. Cellular uptakewas observed. The accumulation of FOL-targeted NPs depends on dual effects of passive andactive targeting. The FOL-targeted PTX NPs showed a greater cytotoxicity against HEC-1Acancer cells in vitro and in vivo, which might be induced by apoptosis. H&E staining did notshowed apparent tissue damage to liver and kidney of the mice after injecting NPsintravenously. These results suggest that the novel FOL-PEG-PLGA NPs could be a potentialdelivery system with excellent therapeutic efficacy for targeting the drugs to cancer cells.(2) Temozolomide-loaded PLGA-based surperparamagnetic nonaparticlesPolysorbate80coated temozolomide-loaded PLGA-based surperparamagneticnonaparticles (TW-TPS-NPs) were successfully synthesized and characterized as a drug carrier and diagnosis agent for brain delivery. TW-TPS-NPs displayed a narrowhydrodynamic particle size distribution with the mean size about220nm. Vibration simplemagnetometer proved that TW-TPS-NPs possessed superparamagnetic characteristic andsatisfied the requirement of MRI. TW-TPS-NPs exhibited high drug loading andencapsulation efficiency as well as good sustained drug release performance for15days.MTT assay demonstrated the antiproliferative effect of TW-TPS-NPs for C6glioma cells.Significant cellular uptake of TW-TPS-NPs was evaluated in C6glioma cells. MRI scanninganalyses in vitro indicated that TW-TPS-NPs could be used as a good MRI contrast agent.(3) Dual docetaxel/superparamagnetic iron oxide loaded nanoparticlesSingle chain prostate stem cell antigen antibodies (scAbPSCA) tumor-targeting polymernanoparticles loaded simultaneously with anticancer drug Dtxl and SPIO nanocrystals weredeveloped for both cancer therapy and ultrasensitive MRI. The diameter of NPs was about147nm and the SPIO and drug encapsulation efficacy was23%and6.02%, respectively.The NPs exhibited a triphasic drug release pattern in vitro. Enhanced cellular uptake abilityand antiproliferative effect of the targeted NPs in prostate cancer PC3cell line were observed.Moreover, the NPs exhibited a good anti-tumor effect and MR imaging functioan in vivo.(4) The tumor cell apoptosis mechanism induced by multi-functional nano-carriersThe tumor cell apoptosis mechanism induced by multi-functional nano-carriers wasanalysised global gene expression gene chip technology. More than2-fold differentexpression genes were screened and preformed gene ontology (GO) analysis. The resultconfirmed up-regulated genes mainly enriched in the apoptosis-related biological processes,while the downregulated genes enriched in immunity, inflammation and other biologicalprocesses. TNFSF10, TIA1and TNFRSF19is directly related to induction of apoptosisbiological process. The molecular mechanism of functional nano-drug carrier system toinduce tumor cell apoptosis may be related to the up-regulation expression of TNFSF10,which induced by death receptor-mediated signal transduction pathways.