Superficial bladder cancer is often managed by transurethral surgical resection, followed by intravesical chemotherapy. Mitomycin C (MMC) and doxorubicin are among the most commonly used drugs. Through a series of preclinical and clinical studies, our research group has established that the efficacy of intravesical MMC or doxorubicin therapy is limited by two factors, i.e., inadequate drug delivery to tumor cells and low chemosensitivity of the more rapidly proliferating tumors. We subsequently identified a method to enhance the delivery of MMC to superficial bladder tumors, and tested this method in an NCI-supported international phase Ill trial in 14 academic centers. The results confirm our hypothesis that maximizing the MMC delivery significantly improves the recurrence-free rate from 23% to 43%. This substantial improvement highlights the importance of drug delivery in this treatment modality and the need of finding an agent that is effective in the remaining majority of the patients. Paclitaxel has a number of properties, which render it a good candidate for intravesical therapy of superficial bladder cancer. Because of its high lipophilicity, paclitaxel (when dissolved in water) penetrates the bladder tissues more readily than MMC or doxorubicin. The strong binding of paclitaxel to macromolecules causes it to be retained in the bladder tissue at high concentrations. Further, paclitaxel is active against human bladder cancer, and shows a higher apoptotic effect in more rapidly proliferating tumors. Paclitaxel is also more active in p53-mutated tumors compared to MMC or doxorubicin. Clearly, development of paclitaxel for intravesical application would be promising. However, as shown by our group, the cremophor micelles in the FDA-approved paclitaxel formulation entraps the drug, and significantly reduces the paclitaxel partitioning into the bladder wall, thus ruling out the use of his formulation. To overcome this problem, we have developed two alternative formulations, which do not use cremophor, allow rapid drug release, show biological activity in human superficial data cancer cells, and enhanced paclitaxel penetration into bladder tissue. The purpose of this application is to develop these paclitaxel-loaded particles and to select one formulation for future clinical evaluation. The proposed studies will (1) develop rapid-release paclitaxel-loaded particles, (2) evaluate the targeting advantage of these particles, and (3) identify the treatment schedule to deliver an effective drug exposure.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Small Business Innovation Research Grants (SBIR) - Phase I (R43)
Project #
5R43CA107743-02
Application #
6923709
Study Section
Special Emphasis Panel (ZCA1-GRB-P (J1))
Program Officer
Fu, Yali
Project Start
2004-08-01
Project End
2008-07-31
Budget Start
2005-08-01
Budget End
2008-07-31
Support Year
2
Fiscal Year
2005
Total Cost
$300,157
Indirect Cost
Name
Optimum Therapeutics, LLC
Department
Type
DUNS #
603887808
City
Columbus
State
OH
Country
United States
Zip Code
Au, Jessie L-S; Yeung, Bertrand Z; Wientjes, Michael G et al. (2016) Delivery of cancer therapeutics to extracellular and intracellular targets: Determinants, barriers, challenges and opportunities. Adv Drug Deliv Rev 97:280-301
Lu, Ze; Yeh, Teng-Kuang; Wang, Jie et al. (2011) Paclitaxel gelatin nanoparticles for intravesical bladder cancer therapy. J Urol 185:1478-83
Yeh, Teng Kuang; Lu, Ze; Wientjes, M Guillaume et al. (2005) Formulating paclitaxel in nanoparticles alters its disposition. Pharm Res 22:867-74