Tumor-targeted Polymersomes to image and Treat Ovarian Cancer

肿瘤靶向聚合物体成像和治疗卵巢癌

• 批准号: 8592768
• 负责人: Zhiliang Cheng
• 金额: $ 34.29万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-13 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8592768
• 关键词: Adnexal Mass; Antineoplastic Agents; Binding; Biocompatible; Biodistribution; Blood Circulation; Cancer Etiology; Cancer cell line; Cessation of life; Contrast Media; Dendrimers; Devices; Diagnosis; Disease; Dose; Drug Delivery Systems; Drug Formulations; Drug Kinetics; Drug toxicity; Early Diagnosis; Early treatment; Effectiveness; Encapsulated; Ethylene Glycols; Gadolinium; Goals; Human; Image; Implant; In Vitro; Label; Lesion; Ligands; Magnetic Resonance; Magnetic Resonance Imaging; Malignant - descriptor; Malignant neoplasm of ovary; Membrane; Mesothelioma; Monitor; Mus; Operative Surgical Procedures; Ovarian; Ovarian Adenocarcinoma; Paclitaxel; Pancreatic Adenocarcinoma; Patients; Pharmaceutical Preparations; Polyethylene Glycols; Property; Proteins; Recombinant Antibody; Screening for Ovarian Cancer; Site; Specificity; Staging; Surface; Survival Rate; Therapeutic; Time; United States; Woman; Yeasts; aqueous; biomaterial compatibility; cancer cell; cytotoxicity; di-block copolymer; ethylene glycol; gadolinium oxide; imaging probe; improved; in vivo; interest; mesothelin; ovarian neoplasm; particle; polycaprolactone; public health relevance; research clinical testing; response; statistics; theranostics; tumor; tumor xenograft; uptake

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.

描述（由申请人提供）：卵巢癌是美国女性癌症死亡的第五大原因，5年生存率低于50%。如果卵巢癌早期发现，5年生存率提高到> 90%。不幸的是，卵巢肿瘤的早期检测和治疗目前受到无法精确诊断和分期疾病的严重阻碍。到目前为止，只有13-21%的接受手术切除附件肿块的妇女实际上患有卵巢癌。在发现肿瘤的患者中，高达90%的明显I期或II期卵巢癌患者没有最佳手术分期，约30%的患者分期不足。这些统计数字强调了需要制定更有效的早期检测和分期策略。该提案的总体目标是开发肿瘤靶向多功能聚合物囊泡，以提高卵巢癌早期检测，分期和治疗的准确性和有效性。为了实现这一目标，一个高灵敏度的磁共振（MR）成像探针将制备从生物可降解的多孔聚合物囊包封钆（Gd）标记的树枝状聚合物。将针对间皮素的人源重组抗体（scFv）缀合至聚合物囊泡表面以赋予对恶性卵巢病变的特异性。间皮素是一种非必需蛋白质，由来自不同来源的癌细胞过度表达，包括卵巢癌和胰腺腺癌以及间皮瘤。疏水抗癌药物紫杉醇将被加载到疏水膜中，成像将用于准确评估和监测给药。据设想，这些多功能装置的使用将提供改善肿瘤早期检测和抗肿瘤功效的希望，同时降低药物毒性和/或剂量。在成功完成该项目后，我们希望有一个安全有效的纳米平台可用于进一步的临床评估。该提议的具体目的是（1）合成Gd包封的、载药的治疗诊断聚合物囊泡;（2）表征抗间皮素- scFV缀合的聚合物囊泡在卵巢癌细胞中的靶向、摄取和体外细胞毒性;和（3）评估各种聚合物囊泡在卵巢肿瘤异种移植物中的对比增强、循环时间、生物分布、保留和抗肿瘤功效。