Rapid release paclitaxel nanoparticles for bladder cancer intravestical therapy

描述（由申请人提供）：膀胱癌是美国第四大常见癌症。在2007年，约有67,160例膀胱癌新病例被诊断出来，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。大约70-80%的膀胱癌患者表现为浅表性肿瘤。浅表性膀胱癌的治疗通常是经尿道切除肿瘤，伴有或不伴有电灼，并辅以膀胱内化疗。经尿道切除治疗的患者中，40%至80%的患者出现复发性肿瘤，10%至20%的复发性疾病出现分级和/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，一个重要的教训是膀胱内丝裂霉素（MMC）或多柔比星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，我们确定了一种优化的方法来增强MMC对浅表性膀胱肿瘤的递送，并在14个学术中心的随机、nci支持的双臂国际III期试验中对该方法进行了测试。结果证实了我们的假设，即最大限度地增加MMC的剂量可以显著提高无复发率，从标准组的23%提高到优化组的43%。这一重大改进突出了在这种治疗方式中充分给药的重要性。剩下的挑战是为不能通过膀胱内MMC治疗的剩余患者（约60%）开发有效的治疗方法。在I期SBIR授权期间，我们评估了几种药物载体，并确定了紫杉醇负载的明胶纳米颗粒（PNP）作为候选药物。已完成的体外和体内研究显示出良好的药物释放和膀胱组织渗透特性，并具有显著的抗肿瘤活性。先前I期SBIR拨款的目标是开发一种适合膀胱内治疗的紫杉醇制剂。选择紫杉醇的另一个优势是由于(a)它具有抗膀胱癌的活性，(b)它是亲脂性的，因此可以很容易地在尿路上皮上分裂，(c)它与组织结合，因此在膀胱内治疗的2小时持续时间后仍能保留，(d)它可以通过p53依赖和独立的途径诱导细胞凋亡，因此在野生型p53或突变型p53对p53有活性的肿瘤中有活性。在p53突变肿瘤中的活性是可取的，因为60%的膀胱肿瘤具有突变的p53，并且因为MMC通过p53依赖途径诱导细胞凋亡，因此对p53突变的肿瘤没有活性。在I期R43拨款期间进行的研究支持使用膀胱内PNP治疗浅表性膀胱癌。目前的II期SBIR申请旨在推动PNP向临床评估的发展。我们建议进行cGMP的制作、分析和测试以满足FDA的要求，GLP临床前毒理学，与FDA进行IND前会议，最终申请IND，设计临床开发策略。公共卫生相关性：目前的建议是开发一种新的治疗方法来治疗癌症，特别是膀胱癌。

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.