Caged micelles for co-delivery of SAHA and geldanamycin in cancer therapy

描述（由申请人提供）：近年来，参与调节基因表达和信号转导途径的蛋白质作为治疗耐药癌症的有希望的靶点产生了巨大的热情。有令人鼓舞的临床前数据显示，这些新的候选药物可以通过新的作用机制选择性地靶向肿瘤细胞，例如辛二酰苯胺异羟肟酸（SAHA）和格尔德霉素（GA）。单独地，每种药物在体外发挥惊人的抗肿瘤活性，但SAHA和GA的组合显示出上级的肿瘤杀伤力。尽管这些新的抗肿瘤药物对分子靶点具有选择性作用，但其特点是肝毒性高，分布广，静脉注射时消除迅速。因此，显然需要通过多功能载体来改进这些令人兴奋的新药的联合治疗技术。从实践的观点看，这可以降低药理学干预所需的治疗剂量，沿着潜在的较低剂量限制性毒性。值得注意的是，单一药物在肿瘤部位的累积是极其具有挑战性的，并且当施用单独的载体或药物用于联合治疗时变得更加如此。尽管并非所有药物组合都需要同时递送（时机可能起关键作用），但SAHA和GA的上级抗肿瘤功效表明，更大的细胞共定位可能在生物肿瘤杀伤中起关键作用。为了验证我们的假设，我们提出了四个广泛的具体目标：（1）合成和表征聚用于GAp包封的（asp-g-ADA）-b-PCL和聚（bCD-PEG）-b-PCL（笼状胶束）和SAHA增溶，并验证交联bCD-ADA壳作为SAHA从bCD空腔解离的扩散屏障的存在，（2）使用已建立的测量难溶于水的化合物的控释的方法，研究GAp和SAHA在不同环境条件下的负载和体外释放动力学，（3）研究使用转铁蛋白靶向笼状胶束的GAp和SAHA共递送在MCF-7（乳腺）和PC-3中的体外抗肿瘤功效。（前列腺）细胞，和（4）在荷瘤小鼠中使用转铁蛋白靶向的笼状胶束研究GAp和SAHA的体内生物学抗肿瘤功效。目前的建议是第一次研究SAHA与GA的联合递送，通过靶向生物相容性多功能载体进行有效的联合治疗，最终的长期目标是改善癌症患者中侵袭性肿瘤的化疗消退。

DESCRIPTION (provided by applicant): In recent years, proteins involved in regulating gene expression and signal transduction pathways have generated tremendous enthusiasm as promising targets for treating resistant cancers. There are encouraging preclinical data revealing that these newer drug candidates can selectively target tumor cells through novel mechanisms of action, e.g. suberoylanilide hydroxamic acid (SAHA) and geldanamycin (GA). Separately each drug exerts astonishing antitumor activity in vitro, but the combination of SAHA and GA demonstrates superior tumor-kill. Despite their selective methods of action on molecular targets, these new antitumor agents are characterized by high liver toxicities, wide distributions, and rapid eliminations when injected IV. There is therefore a clear need to improve the technology for combination therapy of these exciting new drugs through means of a multifunctional carrier. From a practical point of view, this may reduce the therapeutic dosage required for pharmacological intervention along with a potentially lower dose- limiting toxicity. It is significant to note that accumulation of a single drug at a tumor site is extremely challenging, and becomes even more so when a separate carrier or drug is administered for combination therapy. Although not all drug combinations demand simultaneous delivery (timing may play a critical role), the superior antitumor efficacy of SAHA and GA suggests that greater cellular co-localization may play a critical role in biological tumor-kill. To test our hypothesis, we propose four broad specific aims: (1) to synthesize and characterize poly(asp-g-ADA)-b-PCL and poly(bCD-PEG)-b-PCL for GAp encapsulation (caged micelle) and SAHA solubilization, respectively, and to verify the presence of a crosslinked bCD-ADA shell as a diffusion barrier to SAHA dissociations from bCD cavities, (2) to study the loading and in vitro release kinetics of GAp and SAHA under varying environmental conditions using established methods for measuring controlled release of poorly-water soluble compounds, (3) to study the in vitro antitumor efficacy of GAp and SAHA co-delivery using transferrin-targeted caged micelles in MCF-7 (breast) and PC-3 (prostate) cells, and (4) to study the in vivo biological antitumor efficacy of GAp and SAHA using transferrin- targeted caged micelles in tumor-bearing mice. The current proposal is the first of its kind to investigate co-delivery of SAHA in combination with GA via means of a targeted biocompatible multifunctional carrier for effective combination therapy, with the ultimate long-term goal of improving chemotherapeutic regression of aggressive tumors in cancer patients.