Geldanamycin-Mediated Uptake of Nanoparticle Probes

提供的空间） 我们已经开发了与抗癌天然产物结合的荧光纳米颗粒（NP） 格尔德霉素（GA），初步用作研究GA药理作用的分子探针 在肝癌细胞中。GA通过聚合物涂层连接到纳米颗粒，所述聚合物涂层a）改善了机械性能， 所述荧光微球核心的化学稳定性，B）控制所述微球表面上的药物负载， 纳米颗粒，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 通过控制药物的表面载量（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。格尔德霉素敏感性 癌细胞依赖于两种不同的机制，热休克蛋白90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个有趣的选择性探针， 纳米颗粒在动物肿瘤中的摄取。该提案旨在定义GA依赖性细胞摄取， 可用作新型成像探针或多价药物递送的纳米颗粒的肿瘤选择性 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.