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.
Drug resistance, metastases, and adverse side effects are the major causes of treatment failure in ovarian cancer. The work in this application will provide new approaches for suppressing multidrug resistance and outline effective methods of treating primary ovarian tumor and intraperitoneal metastases while preventing adverse side effects on healthy organs and tissues. To this end, novel nontoxic tumor targeted delivery systems will be designed and used for the simultaneous delivery of several anticancer drugs with different mechanisms of action, peptides and antisense oligonucleotides.
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