Development of micelle delivery systems for cancer therapy
Type of DegreePhD Dissertation
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Polymeric micelles have been investigated as nanomedicines for cancer treatment. They can target specific tissues, prolong circulation, and reduce side effects. These features make them a promising delivery system for cancer treatment. This dissertation provides a comprehensive review of different polymeric materials, stimuli-sensitive polymers, clinical trials, and drug delivery applications of polymeric micelles. This dissertation research further uses micellar systems for the codelivery of copper and their ionophores as an effective cancer nanomedicine. Copper ionophores have shown promising results in cancer therapy. These small molecules can bind copper to form copper complexes. There are several advantages of using copper complexes in cancer therapy. Studies showed that some of the copper ionophores such as elesclomol (ES) can synergize some inhibitors to overcome drug resistance. Therefore, developing efficient delivery systems for these copper complexes is crucial. Hence, this dissertation also presents a comprehensive review of ES and its application in cancer therapy. This review will provide guidance for understanding mechanisms of ES and exploring its application. In this research work, we developed an ES-Cu micelle delivery system for enhanced accumulation of ES and Cu in cancer cells. We first developed a D-a-tocopherol polyethylene glycol 1000 succinate/chondroitin sulfate-cholic acid (TPGS/CS-CA) based micelle to encapsulate ES-Cu complex. Our micelle system could achieve ES and copper ions (Cu(II)) self-chelation during the preparation process, instead of synthesizing ES-Cu complex before preparation. Formulation stability was evaluated in order to screen the most stable formulation. The particle sizes of ES-Cu micelles were ~ 15 nm. The ES-Cu micelles were stable in 10% serum for at least 72 h. We performed MTT assay and colony formation assay test its cytotoxicity in 6 cell lines, including 3 drug-resistant cell lines. There was no significant difference of IC50 of ES-Cu micelles in drug-sensitive and drug-resistant cell lines. We also proved that ES-Cu micelles could bypass efflux transporters without affecting their activities to exert its activity. It provides an alternative strategy for drug-resistant cancer therapy. ES-Cu micelles induced reactive oxygen species (ROS) increase and decreased mitochondrial membrane potentials in drug-resistant cells. When culturing Raw 264.7 macrophages with ES-Cu micelle-pretreated drug-resistant cells, it could polarize Raw 264.7 macrophages into M1 phenotype. This ES-Cu micelle delivery system provides a promising method of delivering ES-Cu complex to treat drug-resistant cancers. Next, we developed a novel micelle delivery system for codelivering Cu and DQ (a ROS sensitive diethyldithiocarbamate (DTC) prodrug) for cancer therapy. We first synthesized a DTC prodrug DQ with ROS trigger release ability. The DQ-Cu micelles had a narrow size distribution (PDI ~ 0.1). They were stable in 10% serum for at least 72 h. This DQ-Cu micelle delivery systems was proved to achieve excellent anticancer activity in 3 cell lines. To further enhance its efficacy, b-lapachone (Lap) was used here to combine with DQ-Cu micelles. The combination treatment showed enhanced anticancer activity in 4T1 cells. DTC is one of disulfiram (DSF) metabolites in human body. It can chelate with copper to form Cu(DTC)2 which showed potent efficacy in various cancer cells in several studies. DSF is an FDA proved antialcohol drug, which has showed promising data in cancer therapy. This work provides a promising administration strategy for repurposing DSF in cancer therapy.