Bladder Tumor Targeting by Intravesical Paclitaxel

描述（由申请人提供）：浅表性膀胱癌通常通过经尿道手术切除，然后膀胱内化疗来治疗。丝裂霉素C （MMC）和阿霉素是最常用的药物。通过一系列的临床前和临床研究，我们课课组已经确定膀胱内MMC或阿霉素治疗的疗效受到两个因素的限制，即肿瘤细胞的药物递送不足和更快速增殖的肿瘤的低化学敏感性。随后，我们确定了一种方法来增强MMC对浅表性膀胱肿瘤的递送，并在nci支持的14个学术中心的国际ii期试验中对该方法进行了测试。结果证实了我们的假设，即最大限度地提高MMC的无复发率，从23%提高到43%。这一实质性的改善突出了药物递送在这种治疗方式中的重要性，以及找到一种对其余大多数患者有效的药物的必要性。

DESCRIPTION (provided by applicant): 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.