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: 7493914
• 负责人: GISELLE M KNUDSEN
• 金额: $ 5.13万
• 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 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7493914
• 关键词: Affinity; Affinity Chromatography; Animals; Binding; Biological Assay; Biological Factors; Breast Cancer Detection; Cancer cell line; Cell Line; Cells; Chemical Structure; Confocal Microscopy; Cultured Cells; Detection; Dose; Drug Controls; Drug Delivery Systems; Drug or chemical Tissue Distribution; Fluorescence; Geldanamycin; Gold; HCT116 Cells; Image; In Vitro; Latex; Life; Link; Mechanics; Mediating; Metals; Methods; Molecular Probes; Pathway interactions; Pattern; Pharmaceutical Preparations; Polymers; Proteins; Receptor Cell; Sampling; Signal Transduction; Staging; Structure; Surface; Testing; Toxic effect; Xenograft Model; base; cancer cell; cellular targeting; chemical stability; concept; crosslink; cytotoxicity; design; imaging probe; improved; in vivo; interest; nanocrystal; nanoparticle; neoplastic cell; particle; receptor; research study; response; tumor; uptake

spaceprovided) 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.

提供空间） 我们开发了与抗癌天然产物缀合的荧光纳米颗粒（NP） 格尔德霉素 (GA) 最初用作研究 GA 药理作用的分子探针 在活癌细胞中。 GA 通过聚合物涂层与纳米粒子连接，a) 改善机械性能和 荧光纳米晶核的化学稳定性，b) 控制表面的药物负载 纳米颗粒，c) 允许在细胞内将荧光纳米颗粒无辅助地递送至肿瘤细胞。经过 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 培养癌细胞中药物摄取和细胞毒性的剂量反应。格尔德霉素敏感性 癌细胞依赖于两种不同的机制：Hsp90 特异性识别以及活性 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取。该提案旨在定义 GA 依赖性细胞摄取和 可用作新成像探针或多价药物递送的纳米颗粒的肿瘤选择性 颗粒。