Geldanamycin-Mediated Uptake of Nanoparticle Probes

格尔德霉素介导的纳米颗粒探针的摄取

• 批准号: 7151736
• 负责人: GISELLE M KNUDSEN
• 金额: $ 4.88万
• 依托单位: PURDUE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-01 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7151736
• 关键词: neoplastic cell

DESCRIPTION (provided by applicant): We have developed fluorescent nanoparticles (NP) conjugated to the anticancer natural product geldanamycin (GA) to be used initially as a molecular probe for studying the pharmacological effects of GA in live cancer cells. GA is linked to the nanoparticle via a polymer coating that a) improves mechanical and chemical stability of the fluorescent nanocrystal core, b) controls the drug loading on the surface of the nanoparticle, and c) allows unassisted intracellular delivery of fluorescent nanoparticles to tumor cells. By controlling the surface loading of the drug (from 5 to 300 molecules) we have been able to demonstrate a dose response for both drug uptake and cytotoxicity in cultured cancer cells. Geldanamycin-sensitivity in cancer cells is dependent upon two different mechanisms, Hsp90 specific recognition as well as an active uptake pathway. These two factors make geldanamycin an interesting selective probe for directing nanoparticle uptake in animal tumors. This proposal aims to define the GA-dependent cellular uptake and tumor selectivity of nanoparticles that can be used as new imaging probes or multivalent drug delivery particles.

描述（由申请人提供）：我们开发了与抗癌天然产物格尔德霉素（GA）缀合的荧光纳米颗粒（NP），最初用作研究GA在活癌细胞中的药理学作用的分子探针。GA通过聚合物涂层与纳米颗粒连接，所述聚合物涂层a）改善荧光纳米颗粒核的机械和化学稳定性，B）控制纳米颗粒表面上的药物负载，和c）允许荧光纳米颗粒向肿瘤细胞的无辅助细胞内递送。通过控制药物的表面负载（从5到300个分子），我们已经能够证明培养的癌细胞中药物摄取和细胞毒性的剂量反应。癌细胞对格尔德霉素的敏感性取决于两种不同的机制：Hsp90特异性识别以及主动摄取途径。这两个因素使格尔德霉素成为一种有趣的选择性探针，用于指导动物肿瘤中纳米颗粒的摄入。该提案旨在定义可用作新的成像探针或多价药物递送颗粒的纳米颗粒的GA依赖性细胞摄取和肿瘤选择性。