Molecular targeting of drug delivery systems to ovarian cancer by BH3 and LHRH peptides

Ovarian cancer is the 5th most leading cancer in the United States today, causing the deaths of more than 16000 women in 2004 alone. The current approaches for the treatment of ovarian cancer involve post surgical chemotherapy using systemic and local delivery procedures. Although effective to differing degrees, the majority of the drugs used in chemotherapy suffer from certain common disadvantages: (1) Drug delivery is systemic and therefore not usually directed against specific target sites; (2) The drugs elicit an antiapoptotic response which can result in cancer cell resistance and survival; (3) Low solubility of some drugs.; The primary objective of this study was to develop a multicomponent drug delivery system (DDS) that would overcome the above stated shortcomings. The methods employed tested multiple combinations of the leutinizing hormone releasing hormone (LHRH) peptide, the BCL2 Homology 3 (BH3) peptide, Polyethylene glycol (PEG) polymer and the anticancer drug camptothecin (CPT) in vitro and in vivo on ovarian carcinoma cells (A2780) and animal tumor models respectively. Conjugates of LHRH. BH3, PEG and CPT as well as fusion peptides of antennapedia, LHRH and BH3 were evaluated for cytotoxicity, specificity and overall efficacy. Biological assays were utilized to verify the route of action for the observed effectiveness of the conjugates. Alongside, qualitative methods were also used to establish the localization of the conjugates.; The overall findings demonstrated the specificity of the LHRH moiety for the ovarian cancer cells resulting in effective targeting of the DDS to the desired site. The BH3 peptide overshadowed any effect caused by the activation of antiapoptotic mechanisms by pro survival members of the BCL2 family. PEG increased the solubility of the anticancer drug (CPT) and also acts as a backbone for the bioconjugates.; In conclusion, targeting of an anticancer drug-delivery to the cancer cells by the LHRH peptide enhances the efficacy of chemotherapy and reduces adverse side effects of the drug to healthy tissues. Therefore, the combination, in one DDS, of an anticancer drug, a targeting moiety and a suppressor of antiapoptotic cellular defense has the potential to be a powerful therapeutic anticancer agent.