Nanoparticles-mediated combination therapy for breast cancer

摘要 尽管最近在治疗方面取得了进展，但转移性乳腺癌（mBCa）仍然是乳腺癌的主要原因之一。 美国女性癌症相关死亡人数。化疗仍然是基础， 所有mBCa分子亚型的管理和蒽环类和紫杉烷类是两种主要类型的 化疗药物化疗中的一个主要问题是内在和获得的耐药性。此外，本发明还提供了一种方法， 免疫疗法的总体益处对于mBCa仍然有限。仍然需要制定新的战略 以克服mBCa中的化学抗性和/或免疫疗法的不良反应。IRhom蛋白（iRhom 1 和iRhom 2）是菱形膜内蛋白酶的无催化活性亲属， 在调节其他膜蛋白的稳定性和运输中的作用。IRhom 1在几种细胞中过表达， 包括乳腺癌（BCa）在内的癌症类型和iRhom 1的敲低导致肿瘤的显著抑制 体内生长我们已经证明，iRhom 1的敲除会导致肿瘤细胞对几种药物敏感 化疗剂包括阿霉素（DOX）和SAHA。我们进一步证明了iRhom 1在细胞中起着重要的作用。 iRhom 1在调节肿瘤免疫应答中的作用和iRhom 1的敲除导致肿瘤免疫应答的改善， 微环境为了促进这些新发现的治疗转化，我们开发了一种新的 在选择性共递送iRhom 1 siRNA和化疗剂以 肿瘤的我们还开发了一种生物工程化的iRhom 1 pre-siRNA（pre-siiRhom 1）， 成熟的siRNA。我们进一步开发了DOX-SAHA，一种前药缀合物， 促进协同作用的两种药物的共递送。该应用程序的重点是进一步改善 纳米载体的安全性和肿瘤靶向效率以及 DOX-SAHA/pre-siiRhom 1的共递送。还将研究潜在的机制。三个具体目标 将在这一提案中继续进行。目标1将开发和表征用于共配制的改进的纳米载体 DOX-SAHA和pre-siiRhom 1。目的2研究纳米载体的肿瘤靶向性， 在纳米载体中共配制的DOX-SAHA和pre-siiRhom 1的PK和组织生物分布。目标3将 研究该组合的体内治疗功效、潜在机制和毒性特征 在小鼠和人BCa模型中的治疗。这项研究的成功完成将导致发展 用于治疗包括mBCa在内的不同类型癌症的新组合疗法。

Abstract Despite recent advances in treatment, metastatic breast cancer (mBCa) remains one of the leading causes of cancer-related deaths in the United States among women. Chemotherapy remains fundamental to the management of all molecular subtypes of mBCa and anthracyclines and taxanes are two major types of chemotherapeutics. One major issue in chemotherapy is drug resistance, both intrinsic and acquired. In addition, the overall benefit of immunotherapy remains limited for mBCa. There is still a need to develop novel strategies to overcome chemoresistance and/or the poor response of immunotherapy in mBCa. IRhom proteins (iRhom 1 and iRhom 2) are catalytically inactive relatives of rhomboid intramembrane proteases and play an important role in regulating the stability and trafficking of other membrane proteins. IRhom1 is overexpressed in several types of cancers including breast cancer (BCa) and knockdown of iRhom1 led to significant inhibition of tumor growth in vivo. We have shown that knockdown of iRhom1 led to sensitization of tumor cells to several chemotherapeutic agents including doxorubicin (DOX) and SAHA. We have further shown that iRhom1 plays a role in modulating tumor immune response and knockout of iRhom1 resulted in an improvement in tumor immune microenvironment. To facilitate the therapeutic translation of these novel findings, we have developed a new nanocarrier that is highly effective in selective codelivery of iRhom1 siRNA and chemotherapeutic agents to tumors. We have also developed a bioengineered iRhom1 pre-siRNA (pre-siiRhom1) that is biotransformed to mature siRNA upon intracellular delivery. We have further developed DOX-SAHA, a prodrug conjugate to facilitate codelivery of the two drugs of synergistic action. This application is focused on further improvement of the safety and the tumor-targeting efficiency of the nanocarrier as well as the overall therapeutic efficacy of codelivery of DOX-SAHA/pre-siiRhom1. The underlying mechanism will also be investigated. Three specific aims will be pursued in this proposal. Aim 1 will develop and characterize an improved nanocarrier for co-formulating DOX-SAHA and pre-siiRhom1. Aim 2 will investigate the tumor-targeting efficiency of the nanocarrier, and the PK and tissue biodistribution of DOX-SAHA and pre-siiRhom1 co-formulated in the nanocarrier. Aim 3 will investigate the in vivo therapeutic efficacy, the underlying mechanism, and the toxicity profile of the combination therapy in murine and human BCa models. Successful completion of this study will lead to the development of a new combination therapy for the treatment of different types of cancers including mBCa.