Prostate cancer (PCa) is the most commonly diagnosed malignancy, and the second leading cause of cancer mortality among American males. Although majority of patients with metastatic PCa initially respond to chemical or surgical castration, a significant number will eventually advance to hormone-refractory PCa (HRPC), for which effective treatment is very limited. Paclitaxel (PTX) is a key component of many therapeutic regimens for HRPC. However, the therapeutic potential of PTX is limited by the associated toxicity. In addition, drug resistance may eventually occur in most of the treated patients. Development of a strategy that can simultaneously improve selective delivery of PTX to tumor cells and sensitize the cancer cells to PTX is likely to significantly improve the outcome of the treatment. We have recently developed a novel delivery system that is based on PEG-derivatized embelin. Embelin is a naturally occurring alkyl substituted hydroxyl benzoquinone and a major constituent of Embelia ribes BURM. It shows antitumor activity by itself and sensitizes resistant cancer cells to other chemodrugs largely thorough blocking the activity of X-linked inhibitor of apoptosis protein (XIAP). Like many other chemodrugs, embelin is poorly water soluble. We found that PEG-derivatized embelin, which is developed in our group by total synthesis, forms small-sized micelles (20-30 nm) and shows significantly increased solubility (>200 mg/mL). More importantly, PEG-embelin becomes a highly efficient solubilizing agent for other compounds including PTX and camptothecin. We hypothesize that PEG-embelin conjugates can serve as a safe and dual functional carrier system to achieve additive or synergistic antitumor effect with co-delivered drugs such as PTX. Indeed, our preliminary data showed that delivery of PTX via PEG-embelin micelles led to significant improvement in antitumor activity in vitro and in vivo. This application is focused on examining if the delivery system can be further improved via conjugation with a small molecule ligand for sigma 2 receptor that is overexpressed in various types of cancers including PCa.
Two specific aims will be pursued in this proposal:
Aim 1 : To determine the targeting efficiency and in vivo biodistribution of PTX formulated in PCa-specific nanomicelles;
Aim 2 : To investigate the therapeutic effect of PTX formulated in PCa-specific nanomicelles in an animal model of human PCa. Successful completion of this study may lead to the development of a novel therapy to advance the treatment of prostate cancer.
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