Geldanamycin-Mediated Uptake of Nanoparticle Probes

提供空间) 我们开发了与抗癌天然产物偶联的荧光纳米粒(NP) 格尔达霉素(GA)初步用作分子探针研究GA的药理作用 在活的癌细胞中。GA通过聚合物涂层连接到纳米颗粒上，该聚合物涂层a)改善机械性能并 荧光纳米晶核的化学稳定性，b)控制药物在表面的载药量 纳米颗粒，以及c)允许在细胞内无辅助地将荧光纳米颗粒递送到肿瘤细胞。通过 控制药物的表面负载(从5到300个分子)我们已经能够展示一种 培养的癌细胞对药物摄取和细胞毒性的剂量反应。格尔达那霉素敏感性的临床研究 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。这两个因素使格尔达霉素成为一种有趣的选择性探针 纳米颗粒在动物肿瘤中的摄取。该提案旨在定义依赖GA的细胞摄取和 可作为新的成像探针或多价药物传递的纳米粒的肿瘤选择性 粒子。

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.