Geldanamycin-Mediated Uptake of Nanoparticle Probes

描述（由申请人提供）：我们开发了与抗癌天然产物格尔达霉素（GA）偶联的荧光纳米颗粒（NP），最初用作研究GA在活癌细胞中的药理作用的分子探针。GA通过聚合物涂层与纳米颗粒相连，这可以a)提高荧光纳米晶体核心的机械和化学稳定性，b)控制纳米颗粒表面的药物负载，以及c)允许荧光纳米颗粒在细胞内无辅助递送到肿瘤细胞。通过控制药物的表面负载（从5到300分子），我们已经能够证明在培养的癌细胞中药物摄取和细胞毒性的剂量反应。格尔达那霉素在癌细胞中的敏感性依赖于两种不同的机制，Hsp90特异性识别和主动摄取途径。这两个因素使格尔达霉素成为指导动物肿瘤中纳米颗粒摄取的有趣的选择性探针。本研究旨在确定ga依赖的细胞摄取和纳米颗粒的肿瘤选择性，这些纳米颗粒可以用作新的成像探针或多价药物递送颗粒。

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.