NANOENCAPSULATED SIGNAL TRANSDUCTION INHIBITORS FOR BREAST CANCER

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 信号转导抑制剂（STI）是一类新型抗癌药物，其作用具有高度选择性，作用于癌症进展中不可或缺的分子靶点。这些新STI中的许多是大的（500 Da）和亲脂性的（LogPo/w 5），在制剂中呈现显著的挑战，包括差的水溶性、有限的稳定性、宽的分布体积和非特异性毒性。我们的目标是开发STI的纳米载体制剂，用于癌症的单药和联合治疗，这些制剂对所提出的STI治疗具有高反应性。我们将评估STI格尔德霉素（GA）和雷帕霉素（RAPA）作为单一药物和联合使用安全，生物相容性两亲性嵌段共聚物（ABC）胶束制剂对啮齿动物乳腺癌异种移植物的影响。我们假设ABC胶束将通过避免单核吞噬细胞系统的清除来增强这些强效药物的功效，从而导致通过渗漏的血管在实体瘤中的优先蓄积。据报道，RAPA和GA的组合在体外对多发性骨髓瘤具有协同作用。我们的目的是1）在体外研究这些STI的组合，2）使用胶束纳米载体配制它们，3）在小鼠肿瘤模型中研究这些制剂。总之，本研究旨在使用单一药剂和组合的无毒ABC胶束纳米载体制剂在体外和体内建立RAPA和GA在乳腺癌中的功效，提供用于治疗人类乳腺癌的新型STI的新制剂。

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.