Graduation Date

Fall 12-14-2018

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Pharmaceutical Sciences

First Advisor

Tatiana K. Bronich

Abstract

Breast cancer (BC) remains one of the most frequently diagnosed cancer worldwide. Bone is one of the most common sites and often the first clinical indication of metastatic progression of BC. Current treatments including radiation, surgery, and chemotherapy are rarely curative with limited effect in overall survival. The challenge is true especially for patients with triple-negative BC that are not responsive to receptor-targeted therapy, or patients who had exposure to chemotherapy before and might already gain the resistance to some of the drugs.

Here we took advantage of the aminobisphosphonate, alendronate (ALN), that can bind to the bone mineral efficiently and engineered ALN-decorated polymeric micelles to target Docetaxel (DTX) to bone metastasis. DTX/ALN-m showed high affinity to hydroxyapatite in vitro, exhibited similar cytotoxic activity as free drug and demonstrated the potential to intervene the tumor microenvironment by inhibiting bone resorption and macrophage recruitment. Systemic treatment with the DTX/ALN-m led to significant attenuation of bone metastatic tumor burden and improved survival time in the immunocompetent mouse model of BC dissemination to the bone.

To further improve the efficacy of the metastasis treatment, we developed a micellar formulation of DTX and Dasatinib (Das), an inhibitor of multiple tyrosine kinases. Dual drug-loaded micelles inhibited the osteoclast differentiation, migration of cancer cells, exhibited strong synergy in metastatic BC cell lines and retained the comparable efficacy even in DTX-tolerant cells. Mechanistic studies revealed the connection of drug tolerance to the activation of AMP-activated protein kinase and the role of both drugs in mitigating adaptive resistance. We also demonstrated that this micellar drug combination exerted enhanced antitumor activity delaying the progression of metastatic disease. Overall, the micellar drug carriers provide an effective platform for the treatment of breast cancer bone metastasis by targeting tumor and their microenvironment.

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