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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21CA173887-02
Application #
8655832
Study Section
Nanotechnology Study Section (NANO)
Program Officer
Fu, Yali
Project Start
2013-05-01
Project End
2015-04-30
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Pittsburgh
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Chen, Yichao; Xia, Rui; Huang, Yixian et al. (2016) An immunostimulatory dual-functional nanocarrier that improves cancer immunochemotherapy. Nat Commun 7:13443
Sun, Jingjing; Chen, Yichao; Li, Ke et al. (2016) A prodrug micellar carrier assembled from polymers with pendant farnesyl thiosalicylic acid moieties for improved delivery of paclitaxel. Acta Biomater 43:282-91
Zhang, Peng; Huang, Yixian; Kwon, Yong Tae et al. (2015) PEGylated Fmoc-Amino Acid Conjugates as Effective Nanocarriers for Improved Drug Delivery. Mol Pharm 12:1680-90
Zhang, Peng; Li, Jiang; Ghazwani, Mohammed et al. (2015) Effective co-delivery of doxorubicin and dasatinib using a PEG-Fmoc nanocarrier for combination cancer chemotherapy. Biomaterials 67:104-14
Lu, Jianqin; Liu, Chuang; Wang, Pengcheng et al. (2015) The self-assembling camptothecin-tocopherol prodrug: An effective approach for formulating camptothecin. Biomaterials 62:176-87
Zhang, Yifei; Huang, Yixian; Li, Song (2014) Polymeric micelles: nanocarriers for cancer-targeted drug delivery. AAPS PharmSciTech 15:862-71
Lu, Jianqin; Zhao, Wenchen; Huang, Yixian et al. (2014) Targeted delivery of Doxorubicin by folic acid-decorated dual functional nanocarrier. Mol Pharm 11:4164-78
Zhang, Peng; Lu, Jianqin; Huang, Yixian et al. (2014) Design and evaluation of a PEGylated lipopeptide equipped with drug-interactive motifs as an improved drug carrier. AAPS J 16:114-24
Zhang, Peng; Huang, Yixian; Liu, Hao et al. (2014) A PEG-Fmoc conjugate as a nanocarrier for paclitaxel. Biomaterials 35:7146-56
Zhang, Xiaolan; Huang, Yixian; Zhao, Wenchen et al. (2014) PEG-farnesyl thiosalicylic acid telodendrimer micelles as an improved formulation for targeted delivery of paclitaxel. Mol Pharm 11:2807-14

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