Geldanamycin-Mediated Uptake of Nanoparticle Probes

描述(申请人提供)：我们已经开发出与抗癌天然产物格尔达那霉素(GA)偶联的荧光纳米粒(NP)，最初用于研究GA在活癌细胞中的药理作用。GA通过聚合物涂层连接到纳米颗粒，a)提高荧光纳米晶核心的机械和化学稳定性，b)控制纳米颗粒表面的药物载量，以及c)允许在细胞内无辅助地将荧光纳米颗粒输送到肿瘤细胞。通过控制药物的表面负载(从5到300个分子)，我们已经能够在培养的癌细胞中证明药物摄取和细胞毒性的剂量反应。癌细胞对格尔达霉素的敏感性依赖于两种不同的机制，即Hsp90的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。该提案旨在定义可用作新的成像探针或多价药物传递颗粒的纳米颗粒的GA依赖的细胞摄取和肿瘤选择性。

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.