Targeted Proapoptotic Anticancer Drug Delivery Systems

这是一个跨学科项目的竞争性更新申请，旨在开发新型多功能肿瘤靶向促凋亡抗癌药物递送系统（DDS），以提高治疗多药耐药（MDR）卵巢原发肿瘤和腹腔转移的效率。在过去的支持期间，我们开发并表征了DDS的几种变体，并证明：(1)DDS靶向卵巢癌细胞迫使其特异性积聚在肿瘤细胞中，并且限制了化疗对健康器官的不良副作用；(2)同时增强细胞药物摄取，诱导细胞死亡和抑制抗凋亡细胞防御，将抗癌药物的功效提高到与DDS单个成分单独治疗无法达到的水平。设计的DDS变体在药物敏感肿瘤中特别有效，并防止其对化疗产生耐药性。然而，对于从原发卵巢肿瘤和腹腔腹水中分离出来的具有内在耐多药或在以前的化疗过程中获得耐药的细胞，它们的效率较低。这种耐药是由两个主要机制引起的：(1)药物外排泵消除癌细胞中的有毒物质（泵耐药）和(2)细胞抗凋亡防御的激活（非泵耐药）。我们假设，多重耐药原发性卵巢肿瘤和转移瘤的有效治疗只有通过几种具有不同作用机制的抗癌药物同时抑制两种类型的细胞耐药和细胞死亡诱导才能实现。本研究的主要目的是验证这一假设并开发新的多功能药物输送系统（DDS），该系统将显著提高原发性卵巢癌和腹腔转移的化疗效率，同时对健康器官产生最小的副作用。将利用晚期多药耐药卵巢癌患者的原发肿瘤分离物和腹膜腹水在裸鼠身上建立皮下和腹腔模型，并测试开发的DDS的抗肿瘤功效。

This is a competing renewal application for an interdisciplinary project to develop novel multifunctional tumor targeted proapoptotic anticancer drug delivery systems (DDS) to enhance the efficiency of treatment of multidrug resistant (MDR) ovarian primary tumor and intraperitoneal metastases. In the past period of support, we developed and characterized several variants of DDS and demonstrated that: (1) targeting of DDS to ovarian cancer cells forced its specific accumulation in tumor cells, and limited adverse side effects of chemotherapy on healthy organs; (2) simultaneous enhancement of cellular drug uptake, cell death induction, and a suppression of antiapoptotic cellular defense increased the efficacy of the anticancer drug to a level that cannot be achieved by separate treatment with individual components of DDS. Designed variants of DDS were exceptionally effective in drug sensitive tumors and prevented the development of their resistance to chemotherapy. However, they were less efficient in cells isolated from primary human ovarian tumor and intraperitoneal ascites which possess intrinsic MDR or acquired such resistance during previous courses of chemotherapy. This resistance is caused by two major mechanisms: (1) elimination of toxic substances from cancer cells by drug efflux pumps (pump resistance) and (2) activation of cellular antiapoptotic defense (nonpump resistance). We hypothesized that effective treatment of multidrug resistant primary ovarian tumors and metastases is possible only by the simultaneous tumor specific suppression of both types of cellular resistance and cell death induction by several anticancer agents with different mechanisms of action. The main objective of the proposed research is to verify the hypothesis and develop novel multifunctional drug delivery systems (DDS) that will significantly increase the efficiency of chemotherapy of primary ovarian cancer and intraperitoneal metastases, while inducing minimal side effects in healthy organs. Primary tumor isolates and peritoneal ascites from patients with advanced multidrug resistant ovarian carcinoma will be used to create subcutaneous and intraperitoneal models in nude mice and to test antitumor efficacy of the developed DDS.