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，然后进行膀胱内化疗来治疗。丝裂霉素C（MMC）和阿霉素是最常用的药物。通过一系列临床前和临床研究，我们的研究小组已经确定膀胱内MMC或多柔比星治疗的疗效受到两个因素的限制，即，对肿瘤细胞的药物递送不足以及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，以提高MMC的浅表膀胱肿瘤的交付，并测试了这种方法在国际III期临床试验在14个学术中心的NCI支持。结果证实了我们的假设，即最大限度地提高MMC输送显着提高无复发率从23%到43%。这种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，以及寻找在其余大多数患者中有效的药剂的需要。 紫杉醇具有许多特性，使其成为浅表膀胱癌膀胱内治疗的良好候选药物。由于其高亲脂性，紫杉醇（溶于水时）比MMC或阿霉素更容易渗透膀胱组织。紫杉醇与大分子的强结合导致其以高浓度保留在膀胱组织中。此外，紫杉醇对人膀胱癌有活性，并且在更快速增殖的肿瘤中显示出更高的凋亡作用。与MMC或阿霉素相比，紫杉醇在p53突变的肿瘤中也更活跃。 显然，紫杉醇膀胱内应用的发展将是有前途的。然而，如我们的小组所示，FDA批准的紫杉醇制剂中的Cremophor胶束捕获药物，并显著减少紫杉醇分配到膀胱壁中，从而排除了他的制剂的使用。 为了克服这个问题，我们已经开发了两种替代制剂，其不使用Cremophor，允许快速药物释放，在人浅表癌细胞中显示生物活性，并增强紫杉醇渗透到膀胱组织中。本申请的目的是开发这些紫杉醇负载颗粒，并选择一种制剂用于未来的临床评价。拟议的研究将（1）开发快速释放的紫杉醇负载颗粒，（2）评价这些颗粒的靶向优势，（3）确定提供有效药物暴露的治疗方案。

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.