Date of Award
2024
Document Type
Dissertation
Degree Name
Doctor of Philosophy (Ph.D.)
Department
Pharmaceutical and Chemical Sciences
First Advisor
Xiin Guo
First Committee Member
Xiaoling Li
Second Committee Member
Melanie Felmlee
Third Committee Member
Qinliang Zhao
Fourth Committee Member
Tony (Dongxiao) Zhang
Abstract
Lung cancer remains a leading cause of death worldwide and urges the development of more effective and safer treatment options. Conventional platinum-based drugs like cisplatin, while effective, are associated with significant systemic toxicity, particularly nephrotoxicity. Nano formulations, such as liposomal and micellar delivery systems, represent a promising approach to enhance the anticancer activity and reduce the toxicity of platinum complexes.
This study develops and evaluates novel miriplatin-loaded nano formulations for lung cancer therapy. We prepared and screened various liposomal and micellar formulations of miriplatin by either thin-film hydration or co-solvent evaporation, which identified a number of formulations with appropriate sizes and platinum loading for further anticancer activity studies against A549-iRFP multicellular spheroids (MCS), and in an orthotopic lung cancer mouse model. Our findings showed that miriplatin was oxidized during co-solvent evaporation, and the resultant micelles loaded with oxidized miriplatin (M-se-DSPE and M-se-DOPE) exhibited significantly stronger anticancer activity against A549-iRFP MCS compared to cisplatin. In the orthotopic lung cancer model, M-se-DSPE demonstrated comparable efficacy to cisplatin in slowing the tumor progression and metastasis, while reducing the renal toxicity. M-se-DSPE achieved higher plasma exposure, slower clearance and smaller volume of distribution. This study highlights the therapeutic potential of micelles loaded with oxidized miriplatin, owing to their better efficacy and safety.
Pages
139
Recommended Citation
Xu, Zizhao. (2024). Development of Nano Formulations of Lipophilic Platinum Complexes against Lung Cancer. University of the Pacific, Dissertation. https://scholarlycommons.pacific.edu/uop_etds/4310
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