NANOENCAPSULATED SIGNAL TRANSDUCTION INHIBITORS FOR BREAST CANCER

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 信号转导抑制剂(STI)是一类新型的抗癌药物，具有高度的选择性，作用于癌症进展中不可或缺的分子靶点。其中许多新的STI是大的(500 Da)和亲脂的(LogPo/w 5)，在配方上提出了巨大的挑战，包括较差的水溶解度、有限的稳定性、广泛的分布体积和非特异性毒性。我们的目标是开发STI的纳米载体配方，用于癌症的单剂和联合治疗，对建议的STI治疗高度敏感。我们将使用安全、生物相容的两亲嵌段共聚物(ABC)胶束配方，评估STIs、格尔达霉素(GA)和雷帕霉素(RAPA)作为单一药物和联合使用对抗啮齿动物乳腺癌移植瘤的作用。我们假设ABC胶束将通过避免被单核巨噬细胞系统清除，从而通过泄漏的血管在实体肿瘤中优先聚集，从而增强这些强效药物的疗效。据报道，RAPA和GA在体外联合治疗多发性骨髓瘤具有协同作用。我们的目标是1)在体外研究这些STI的组合，2)使用胶束纳米载体来配制它们，3)在小鼠肿瘤模型中研究这些配方。综上所述，本研究试图通过使用无毒的ABC胶束纳米载体制剂的单药和联合制剂，在体内外建立RAPA和GA对乳腺癌的疗效，为人类乳腺癌的治疗提供新的STI配方。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Signal transduction inhibitors (STIs) are a new class of anticancer agents that are highly selective in their action, acting on molecular targets that are integral in the progression of cancer. Many of these new STIs are large (500 Da) and lipophilic (LogPo/w 5) presenting significant challenges in formulation, including poor water solubility, limited stability, wide volumes of distribution, and non-specific toxicities. Our goal is to develop nanocarrier formulations of STIs for single agent and combination therapy in cancers, which are high responsive to treatment with the proposed STIs. We will evaluate the STIs geldanamycin (GA) and rapamycin (RAPA) as single agents and in combination against rodent breast cancer xenografts using a safe, biocompatible amphiphilic block copolymer (ABC) micelle formulation. We hypothesize ABC micelles will enhance the efficacy of these potent agents by avoiding clearance by the mononuclear phagocyte system, resulting in preferential accumulation at solid tumors through leaky blood vessels. Combination of RAPA and GA is reported to be synergistic in vitro against multiple myeloma. Our aims are to 1) investigate the combination of these STIs in vitro, 2) formulate them using a micelle nanocarrier, and 3) investigate these formulations in vivo in murine tumor models. In summary, this study seeks to establish the efficacy of RAPA and GA in breast cancer in vitro and in vivo using nontoxic ABC micelle nanocarrier formulations of single agents and combinations, providing new formulations of novel STIs for treatment of breast cancer in humans.