Tumor-targeted Polymersomes to image and Treat Ovarian Cancer

描述(申请人提供)：卵巢癌是美国女性癌症死亡的第五大原因，5年生存率不到50%。如果卵巢癌被及早发现，5年存活率将提高到90%。不幸的是，由于无法准确诊断和分期，卵巢肿瘤的早期发现和治疗目前正受到严重阻碍。到目前为止，接受手术切除附件肿块的女性中，只有13%-21%的人实际上患有卵巢癌。在发现肿瘤的患者中，高达90%的明显的I期或II期卵巢癌患者没有最佳的手术分期，而大约30%的患者没有得到最佳的手术分期。这些统计数据突出表明，需要制定更有效的战略，以便及早发现和分期。这项建议的总体目标是开发肿瘤靶向多功能多聚体，以提高卵巢癌早期发现、分期和治疗的准确性和有效性。为了实现这一目标，将从可生物降解的多孔聚合物中制备一种高灵敏的磁共振(MR)成像探针。针对间皮蛋白的人类来源的重组抗体(ScFv)将被连接到多聚体表面，以赋予恶性卵巢病变的特异性。间硫蛋白是一种非必需的蛋白质，由来自不同来源的癌细胞过度表达，包括卵巢癌、胰腺癌和间皮瘤。疏水性抗癌药物紫杉醇将被加载到疏水膜中，并将使用成像来准确评估和监测剂量。可以预见，这些多功能设备的使用将提供改善肿瘤早期检测和抗肿瘤疗效的前景，同时减少药物毒性和/或剂量。在这个项目成功完成后，我们预计将有一个安全有效的纳米平台可用于进一步的临床评估。该方案的具体目标是：(1)合成Gd包埋的载药治疗聚合体；(2)表征抗间皮蛋白-单链抗体结合聚合体在卵巢癌细胞中的靶向性、摄取和体外细胞毒性；(3)评价不同聚合体在卵巢肿瘤移植瘤中的对比度增强、循环时间、生物分布、滞留和抗肿瘤效果。

DESCRIPTION (provided by applicant): Ovarian cancer is the fifth leading cause of cancer death among women in the United States and the 5-year survival rate is less than 50%. If ovarian cancer is found early, the 5-year survival rate is improved to >90%. Unfortunately, ovarian tumor early detection and treatment is currently being severely hampered by an inability to precisely diagnose and stage disease. Thus far, only 13-21% of the women that undergo surgery to remove adnexal masses actually have ovarian cancer. In patients where tumors are found, up to 90% of patients with apparent stage I or II ovarian cancer do not have optimal surgical staging, and approximately 30% are understaged. These statistics underscore the need to develop more effective strategies for early detection and staging. The overall goal of this proposal is to develop tumor-targeted multifunctional polymersomes for greater accuracy and effectiveness in ovarian cancer early detection, staging, and treatment. In attempt to achieve this goal, a highly sensitive magnetic resonance (MR) imaging probe will be prepared from biodegradable porous polymersomes with encapsulated gadolinium (Gd)-labeled dendrimers. A recombinant antibody (scFv) of human origin that is directed against mesothelin will be conjugated to the polymersome surface to confer specificity for malignant ovarian lesions. Mesothelin is a non-essential protein that is over-expressed by cancer cells from diverse origins, including ovarian and pancreatic adenocarcinomas and mesotheliomas. The hydrophobic anticancer drug paclitaxel will be loaded into the hydrophobic membrane and imaging will be used to accurately assess and monitor dosing. It is envisioned that the use of these multifunctional devices will offer the promise of improved tumor early detection and antitumor efficacy, while reducing drug toxicity, and/or dose. Upon the successful completion of this project, we expect to have a safe and effective nanoplatform available for further clinical evaluation. The specific aims for this proposal are (1) synthesize Gd-encapsulated, drug- loaded theranostic polymersomes; (2) characterize targeting, uptake and in vitro cytotoxicity of anti-mesothelin- scFV conjugated polymersomes in ovarian cancer cells; and (3) evaluate the contrast enhancement, circulation time, biodistribution, retention and antitumor efficacy of the various polymersomes in ovarian tumor xenografts.