Background: Ovarian cancer is the fourth most frequent cause of cancer death among women and it ranks second among the gynecological malignancies accounting 4% of all cancers in women in United States.. The first line of chemotherapy for ovarian cancer comprises of cisplatin-paclitaxel combination therapy. However, these drugs are associated with severe toxic side effects, for instance, cisplatin shows neurotoxicity, nephrotoxicity and emesis, limiting their usage. About 75% of the late stage ovarian cancer patients do not respond to the conventional therapy either due to development of resistance to chemotherapy or the inefficient treatment of the residual disease. Therefore, the present proposal aims at efficiently eradicating or controlling these micro tumors by a multistep targeting approach using dendrimers as carriers for the intraperitoneal delivery of cisplatin. Rationale: We propose a novel therapeutic strategy that could serve as an adjunct therapy to the existing primary modes of the ovarian cancer therapyto increase the life span and to improve the quality of life of the ovarian cancer patients. Our strategy involves administration of the bispecific antibodies with specificity for both Ovarian cancer associated antigen (CA-125) and biotin. The bispecific antibody binds to the tumor surface. This step is followed by the administration of drug loaded biotinylated, polyamine conjugated dendrimers to target the drug to the cancer cells. The pretargeting strategy provides high dose of the drug to the tumors previously targeted by the bispecific antibody resulting in better efficacy and reduced toxicity. Research Design: The bispecific antibodies will be prepared by chemical cross linking and they will be purified by Column chromatography. The purity of the bispecific antibody will be tested by SDS PAGE and the immunoreactivity will be tested by binding studies with OVCAR-3 cells using ELISA and Confocal microscopy ii) Kinetics of the uptake of bispecific antibodies by the tumor cells will be perfdormed by Confocal microscopy iii) Polyamines will be conjugated to the carboxy terminals of the dendrimers by EDC coupling reaction and their efficiency of drug loading will be tested by HPLC method iv)The pretargeting strategy will be evaluated in NIH OVCAR-3 nude mice. Relevance: The Five year survival rate of the late stage ovarian cancer patients is only 44%. We propose an efficient treatment strategy to increase these late stage ovarian cancer patients and also to improve their quality of life. This novel approach reduces the toxic side effects associated with the chemotherapeutics used for the ovarian cancer treatment. ? ? ? ?
