The proposed studies will evaluate a novel method for targeted delivery of resveratrol alone or in combination with docetaxel at desired rates. Our preliminary studies show, nano-formulated resveratrol can be made to bind high affinity folate receptors on prostate cancer (PCa) cells via folate conjugated poly (?- caprolactone)/poly (ethylene glycol) co-polymer coating of the PBM nanoparticles. We have used a natural polysaccharide (i.e., starch;which is FDA approved) as a core for PBM nanoparticles. These particles have shown, in our preliminary studies, to be rapidly internalized and induce significant cancer cell death at lower doses, than compared to unformulated resveratrol. Importantly, negative controls showed that PBM nanoparticles without resveratrol or docetaxel have no toxic effects on PCa cells. Our exciting preliminary data show that resveratrol potently synergizes with docetaxel to inhibit proliferation and induce cell death in hormone-refractory prostate cancer cells. Since docetaxel is associated with various debilitating toxicities at its maximum tolerated doses besides other formulation issues, a synergistic combination of resveratrol-docetaxel could provide a more potent therapeutic effect at lower drug concentrations that are less likely to result in severe toxicity. Our in vitro data strongly suggest that we can reduce dos levels of docetaxel and compensate it with non-toxic resveratrol. This resveratrol-docetaxel combination uniquely presents 'chemotherapy lite'and low 'chronic'doses instead of 'intermittent maximal doses'would not allow the tumor 'to recover'and thus maximize antitumor outcomes without compromising the quality of life. Through this application, we propose to test this hypothesis by evaluating in vivo potential synergistic effects of resveratrol-docetaxel in inhibiting skeletal metastases of androgen-independent or dependent prostate cancer noninvasively in preclinical mice models. We are optimistic that the successful completion of these studies would directly impact the development of successful treatment strategies using resveratrol as a single agent and/or in combination with lower doses of docetaxel for this pernicious disease with a focus on disease-free survival with diminished toxicity.
Major focus of this study is to overcome the challenges resveratrol and docetaxel has faced in clinics. To resolve this issue we have proposed to improve bioavailability of resveratrol as well as reduce the dose of docetaxel by their combination and targeted delivery specific to the prostate cancer cells. Completion of this study will enable immediate use of combination of docetaxel with resveratrol in clinical settings.