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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Enhancement Award (SC1)
Project #
1SC1CA193758-01
Application #
8739951
Study Section
Special Emphasis Panel (ZGM1)
Program Officer
Vallejo-Estrada, Yolanda
Project Start
2014-09-01
Project End
2018-08-30
Budget Start
2014-09-01
Budget End
2015-08-30
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Morehouse School of Medicine
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
City
Atlanta
State
GA
Country
United States
Zip Code
30310
Singh, Santosh Kumar; Singh, Shriti; Lillard Jr, James W et al. (2017) Drug delivery approaches for breast cancer. Int J Nanomedicine 12:6205-6218
Singh, Santosh K; Lillard Jr, James W; Singh, Rajesh (2017) Molecular basis for prostate cancer racial disparities. Front Biosci (Landmark Ed) 22:428-450
Singh, Shriti; Singh, Santosh Kumar; Chowdhury, Indrajit et al. (2017) Understanding the Mechanism of Bacterial Biofilms Resistance to Antimicrobial Agents. Open Microbiol J 11:53-62
Singh, Santosh Kumar; Banerjee, Saswati; Acosta, Edward P et al. (2017) Resveratrol induces cell cycle arrest and apoptosis with docetaxel in prostate cancer cells via a p53/ p21WAF1/CIP1 and p27KIP1 pathway. Oncotarget 8:17216-17228
Banerjee, Saswati; Singh, Santosh K; Chowdhury, Indrajit et al. (2017) Combinatorial effect of curcumin with docetaxel modulates apoptotic and cell survival molecules in prostate cancer. Front Biosci (Elite Ed) 9:235-245