Therapeutic Targeting Agents for Ovarian Cancer

卵巢癌的治疗靶向药物

• 批准号: 6955302
• 负责人: KIT S LAM
• 金额: $ 32.89万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-25 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6955302
• 关键词: antineoplastics; athymic mouse; cell line; clinical research; combinatorial chemistry; doxorubicin; drug design /synthesis /production; human tissue; integrins; neoplastic cell; ovary neoplasms; peptide library; radiotracer

DESCRIPTION (provided by applicant): The overall goal of this R01 application is to develop high-affinity and high-specificity targeting agents for ovarian cancer. We hypothesize that (I) alpha3beta1 integrin is an excellent therapeutic target for ovarian cancer, (ii) the D-amino acid containing cyclic peptide leads that have already been identified in our laboratory, after further optimization, will become effective therapeutic agents for human ovarian cancer, (iii) some of these peptides, in oligomeric form (either homopolymer or heteropolymer) may be able to cross-link cell surface molecules resulting in higher avidity and possibly causing cell signaling and cellular responses. We believe these targeting agents, when radiolabeled (e.g. with 90Y) or conjugated to liposomes containing chemotherapeutic agents such as doxorubicin (e.g. Doxil(r)), can be used as highly specific therapeutic agents for ovarian cancer. Through screening one-bead one-compound combinatorial peptide libraries, we have already identified peptide ligands that can target ovarian cancer in the xenograft model. In this application, we propose to use combinatorial chemistry, molecular modeling methods, and other biophysical techniques to further optimize our lead compounds, and to characterize the compounds with respect to binding specificity and affinity of, as well as their biochemical effects on, normal and malignant ovarian cancer cells. We believe these peptides, when conjugated onto the surface of Doxil(r), will be able to facilitate the delivery of doxorubicin to the tumor, and therefore will preferentially kill the tumor cells.

描述（由申请人提供）：R01应用程序的总体目标是开发卵巢癌的高亲和力和高特异性靶向剂。我们假设（i）（i）α3Beta1整联蛋白是卵巢癌的极好的治疗靶点，（ii）含有环状肽铅的D-氨基酸在我们实验室进一步优化后已在我们的实验室中已经鉴定出的d-氨基酸，将成为人类卵巢癌的有效治疗剂，或者可能是这些卵巢癌（III）（ii II），或者是Oligipers（iii），或者是Oligigement（III），或者交联细胞表面分子导致较高的亲和力，并可能导致细胞信号传导和细胞反应。我们认为，当放射性标记（例如90岁）或与含有化学治疗剂（例如阿霉素（例如doxil（r））的脂质体相结合时，这些靶向剂可以用作卵巢癌的高度特异性治疗剂。通过筛选单珠一体化合物组合肽库，我们已经确定了可以在异种移植模型中靶向卵巢癌的肽配体。在此应用中，我们建议使用组合化学，分子建模方法和其他生物物理技术来进一步优化我们的铅化合物，并针对结合特异性和亲和力以及对正常和恶性卵巢卵巢卵巢癌细胞的生化特异性和生化作用来表征化合物。 我们认为，当将这些肽结合到多克西尔（R）表面时，将能够促进阿霉素递送到肿瘤上，因此优先杀死肿瘤细胞。