Access Type

Open Access Dissertation

Date of Award

January 2018

Degree Type

Dissertation

Degree Name

Ph.D.

Department

Pharmaceutical Sciences

First Advisor

Arun K. Iyer

Abstract

Renal Cell Carcinoma (RCC) contributes to more than 90% of the most common form of kidney tumor and remains one of the ten leading causes of cancer death in the United States. Although surgery remains an option for operable tumors, high metastatic index and resistance to radiation and chemotherapies prompted recent development of therapeutics that target the RCC angiogenesis and cell proliferation pathways. Tyrosine kinase inhibitors or TKIs (Cabozantinib, Axitinib, Sorafenib, and Sunitinib) and mammalian target of rapamycin (mTOR) inhibitors (Temsirolimus and Everolimus) have increased the therapeutic options for treating RCC. Although the impact towards decreasing disease progression is encouraging, a substantial proportion of patients do not respond adequately, and therapy resistance almost inevitably occurs. Eventually, new strategies with encouraging results have emerged that include immunotherapy, such as the programmed death-1 inhibitor (Nivolumab), cytokines, and a combination of chemo-immune therapy. Nevertheless, the 5-year disease free progression remains a meager <10% and these medicines produce fetal toxicity, contributing to poor overall prognosis. Thus, developing alternative strategies with effective treatment options remains an urgent unmet need for therapy-resistant RCC.

In this regard, combination treatment targeting different cancer survival pathway of tumor microenvironment can be advantageous. Along these lines, we have pursued different combination drug regimens, including inhibitors that target mTOR (everolimus) and RTK or VEGFR (cabozantinib or sorafenib), as possible treatment strategies. In addition, we explored the rational design of nanoparticles to selectively deliver a variety of therapeutic payloads to target hypoxic tumor microenvironment overexpressing carbonic anhydrase-IX (CAIX). Our strategy involved establishing a library of tumor penetrating nanocarriers carrying combination drug payload of RTK-inhibitor with our own apoptosis inducer/CARP-1 protein functional mimetics (CFM-4.16). Nano-carriers were tailored to have varying composition and size that could: (i) efficiently reach the tumor core; (ii) target tumor multi-components including cancer epithelial cells and tumor-associated macrophages (TAM) for overcoming drug resistance in RCC. Specifically, the current work was focused on multimodal approaches, including (a) Optimization of hypoxia marker (CA IX) targeted polymer-lipid nano-formulation (PLNP) using copper-free ‘click’ chemistry; (b) In vitro and in vivo pre-clinical imaging and therapy of PLNP loaded with multiple drugs in inhibiting RCCs using mice bearing resistant RCCs and human cancer mimicking patient-derived xenografts (PDx). The results of antitumor efficacy and biodistribution of targeted PLNPs in animals bearing RCC xenograft and PDx models revealed selective accumulation of drugs at tumor sites resulting in greater tumor growth inhibition with reduced side effects. The highlights of the targeted formulation include specific tumor uptake, faster normal tissue clearance, and less healthy organ uptake. These findings portent promising therapeutic potentials for our newly developed hypoxia-targeted -PLNPs loaded with CFM-4.16 in combination with RTK-inhibitor for effective RCC therapy in the clinic.

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