Rapid release paclitaxel nanoparticles for bladder cancer intravestical therapy

描述(申请人提供)：膀胱癌是美国第四大常见癌症。2007年，约67,160例新诊断的膀胱癌病例将被诊断出来，13,750名患者将死于这些疾病。移行细胞癌占膀胱癌的90%以上。约70%-80%的膀胱癌患者存在浅表肿瘤。浅表性膀胱癌的治疗通常采用经尿道肿瘤电切术加或不加电灼术，辅以膀胱内化疗。经尿道电切术治疗的患者中，40%至80%的患者出现复发肿瘤，10%至20%的复发疾病出现分级和/或分期进展。膀胱内免疫治疗和化疗可降低疾病复发率。通过一系列的临床前和临床研究，一个重要的教训是，丝裂霉素(MMC)或阿霉素膀胱内治疗的疗效受到两个因素的限制，即对肿瘤细胞的药物输送不足和快速增殖的肿瘤的低化疗敏感性。随后，我们确定了一种优化的方法来增强MMC对浅表性膀胱肿瘤的输送，并在14个学术中心的随机、双臂NCI支持的国际III期试验中测试了该方法。结果证实了我们的假设，即最大化MMC交付显著提高了无复发率，从标准ARM的23%提高到优化ARM的43%。这一实质性的改善突出了在这种治疗方式中充分给药的重要性。剩下的挑战是为剩余的患者(~60%)开发一种有效的治疗方法，这些患者无法通过膀胱内MMC进行管理。在第一阶段的SBIR资助中，我们评估了几种药物载体，并确定了紫杉醇明胶纳米粒(PNP)为候选药物。已完成的体外和体内研究显示良好的药物释放和膀胱组织渗透特性，以及显著的抗肿瘤活性。前一期SBIR赠款的目标是开发一种适合膀胱内治疗的紫杉醇配方。选择紫杉醇的另一个优势是：(A)它具有抗膀胱癌的活性，(B)它是亲脂性的，因此很容易在尿路上皮细胞中分配，(C)它与组织结合，因此在膀胱内治疗2小时后仍能保留，以及(D)它能通过p53依赖和不依赖的途径诱导细胞凋亡，因此在野生型P53或突变的P53抗P53的肿瘤中是活跃的。P53突变肿瘤的活性是可取的，因为60%的膀胱肿瘤有突变的P53，因为MMC通过依赖于P53的途径诱导细胞凋亡，因此对突变的P53的肿瘤没有活性。在第一阶段R43拨款期间进行的研究支持使用PNP膀胱内注射治疗浅表性膀胱癌。目前的第二阶段SBIR应用旨在将PNP的开发推向临床评估。我们建议进行cGMP的制造、分析和测试，以满足FDA的要求，GLP临床前毒理学，IND前与FDA的会议，最终的IND备案，以及临床开发战略的设计。与公共卫生相关：目前的建议是开发一种新的治疗癌症的方法，特别是关注膀胱癌。

DESCRIPTION (provided by applicant): Bladder cancer is the fourth most common cancer in the United States. In 2007, about 67,160 new cases of bladder cancer will be diagnosed and 13,750 patients will die of these diseases. Transitional cell carcinoma accounts for more than 90% of bladder cancers. Approximately 70-80% of bladder cancer patients present with superficial tumors. Superficial bladder cancer is managed usually by transurethral resection of the tumor with or without fulguration, and adjuvant intravesical chemotherapy. Between 40 to 80% of patients treated by transurethral resection develop recurrent tumors, and between 10 to 20% of recurrent disease present with grade and/or stage progression. Intravesical immunotherapy and chemotherapy reduces the disease recurrence rate. Through a series of preclinical and clinical studies, an important lesson learned is that the efficacy of intravesical mitomycin (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 an optimized method to enhance the delivery of MMC to superficial bladder tumors, and tested this method in a randomized, two-arm NCI-supported international phase III trial in 14 academic centers. The results confirm our hypothesis that maximizing the MMC delivery significantly improves the recurrence-free rate, from 23% in the standard arm to 43% in the optimized arm. This substantial improvement highlights the importance of adequate drug delivery in this treatment modality. The remaining challenge is to develop an effective treatment for the remaining patients (~60%) who cannot be managed by intravesical MMC. During the Phase I SBIR grant, we evaluated several drug carriers and identified paclitaxel-loaded gelatin nanoparticles (PNP) as the candidate. The completed in vitro and in vivo studies showed favorable drug release and bladder tissue penetration properties, and significant antitumor activity. The goal of the previous Phase I SBIR grant was to develop a formulation of paclitaxel suitable for intravesical treatment. An added advantage of selecting paclitaxel is due to (a) it has activity against bladder cancer, (b) it is lipophilic and therefore can readily partition across the urothelium, (c) it binds to tissues and therefore is retained beyond the 2-hr duration of the intravesical therapy, and (d) it can induce apoptosis through p53-dependent and -independent pathways and is therefore active in tumors with wild type p53 or mutated p53 activity against p53. The activity in p53-mutated tumors is desirable as 60% of bladder tumors has mutated p53 and because MMC induces apoptosis through p53-dependent pathways and is therefore not active against tumors with mutated p53. Studies conducted during the phase I R43 grant support the use of intravesical PNP for the treatment of superficial bladder cancer. The present phase II SBIR application is directed at advancing the development of PNP toward clinical evaluation. We proposed to conduct cGMP manufacturing, analysis and testing to meet FDA requirement, GLP preclinical toxicology, pre-IND meeting with FDA, final IND filing, and design of clinical development strategy. PUBLIC HEALTH RELEVANCE:The current proposal is to develop a novel therapeutic approach to treat cancer, with a focus on bladder cancers in particular.