Nano-cocktail overcomes multidrug-resistance for ovarian cancer therapy

 描述（由申请人提供）：卵巢癌是女性癌症相关死亡的第五大常见原因，导致的死亡人数超过女性生殖系统的任何其他癌症。卵巢癌高死亡率的主要原因是多药耐药性和癌症干细胞（CSC）的转移性。由于传统的抗癌药物不能杀死耐药细胞和消除CSC，因此迫切需要一种新的有效治疗卵巢癌的方法。本研究的目的是开发一种双靶向纳米鸡尾酒（DTNC），用于安全有效的卵巢癌治疗。我们假设：（a）两种靶向部分的低密度组合可以使非特异性靶向作用最小化，同时确保药物载体将仅定位于肿瘤组织中并通过异源多价结合被癌细胞摄取;（B）不同抗癌机制的药物组合将表现出协同作用并根除卵巢肿瘤。我们的项目有三个具体目标。在目标1中，我们将探索最佳癌细胞增殖抑制作用的药物组合。目的2将检查双配体靶向作用， 研究了DTNC的体内分布及药代动力学特征。目的3评价DTNC对小鼠皮下移植瘤和原位腹腔移植瘤的生长抑制作用及全身毒性。在这个为期3年的项目过程中，本科生，研究生和药学博士的学生将参与该项目的各个层面，从动手技能与国家的最先进的设备创造性思维。本科生将从南卡罗来纳州大学的高度选择性的荣誉学院和生物医学工程项目，以及莫里斯学院，一个历史上的黑人，男女同校的学院招募。因此，DTNC的发展将为临床医生提供更有效的工具来对抗卵巢癌，并为学生，特别是代表性不足的少数民族学生提供宝贵的生物医学研究培训机会。

 DESCRIPTION (provided by applicant): Ovarian cancer is the fifth most common cause of cancer-related deaths in women and results in more deaths than any other cancer of the female reproductive system. The primary reasons for the high death rate of ovarian cancer are multidrug-resistance and the metastatic nature of cancer stem cells (CSCs). Since conventional anticancer drugs cannot kill drug resistant cells and eliminate CSCs, a novel effective treatment for ovarian cancer is urgently needed. The objective of this research is to develop a dual targeted nano-cocktail (DTNC) for safe and effective ovarian cancer therapy. We hypothesize that: (a) the low density combination of two targeting moieties can minimize the non-specific targeting effect while ensuring that the drug carrier will be exclusively localized in the tumor tissue and taken up by cancer cells through hetero-multivalent binding; (b) the drug combination of different anticancer mechanisms will exhibit synergistic effects and eradicate ovarian tumor. Our project has three specific aims. In Aim 1, we will explore drug combinations for optimal cancer cell proliferation inhibitory effect. Aim 2 will examine the dual-ligand targeting effect on the biodistribution of DTNC and investigate its pharmacokinetic properties. Aim 3 will evaluate the tumor growth inhibitory effect of DTNC in both subcutaneous xenograft and orthotopic intraperitoneal tumor mouse models and examine its systemic toxicity. Over the course of this 3-year project, undergraduate, graduate, and Doctor of Pharmacy students will participate in the project in various levels, from hands-on skills with state-of-arts equipment to creative thinking. Undergraduate students will be recruited from the highly selective Honors College and Biomedical Engineering program of the University of South Carolina, as well as Morris College, a Historically Black, coeducational college. Therefore, the development of DTNC will provide clinicians with a more effective tool in fighting against ovarian cancer as well as offer precious biomedical research training opportunities for students, especially underrepresented minority students.