Abstract 4538: Multivalent targeting based delivery of therapeutic peptide using AP1-ELP carrier for effective cancer therapy

Abstract The main objectives of drug delivery for almost all cancer therapies are to improve the therapeutic index of anticancer drugs by increasing the amount of drug delivered to the specific tumor site and decreasing its exposure to healthy tissues. Elastin like Polypeptides (ELPs) retain all the advantages of polymeric drug delivery systems, as they are composed of non-toxic and biodegradable amino acid, derived from mammalian tropoelastin. IL-4 receptors (IL-4R) are found to be highly expressed in a wide variety of human tumors and studies have reported that IL-4/IL-4R interactions amplify the expression of some anti-apoptotic proteins, so prevent drug-induced cancer cell death. Thus we have designed multivalent IL-4R targeted based macromolecular carriers, AP1-ELP polymers, in order to examine the therapeutic efficacy in delivering the therapeutic peptide (KLAKLAK)2 to tumor cells. As for the study AP1-ELP polymer, containing six IL-4R binding peptide (AP1) was conjugated with proapoptotic peptide (KLAKLAK)2 on the C-terminal site by cloning. The resultant AP1-ELP-(KLAKLAK)2 construct was successfully expressed and purified from E coli using inverse temperature cycling method. Confocal imaging verified the better cellular accumulation of AP1-ELP-(KLAKLAK)2 in IL-4R highly expressing cancer cells. The cytotoxic effect towards IL-4R highly expressing tumor cells were highly enhanced when treated with AP1-ELP-(KLAKLAK)2 compared to control. FACS analysis data confirmed the significant increase of apoptotic cells when treated with AP1-ELP-(KLAKLAK)2 compared to ELP-(KLAKLAK)2 in dose dependent manner. Ex vivo biodistridution study displayed an increase in intra-tumoral uptake and localization of FNR-675 labeled AP1-ELP-(KLAKLAK)2 than ELP-(KLAKLAK)2. Additionally, AP1-ELP-(KLAKLAK)2 significantly inhibit the tumor growth when injected intravenously in MDA-MB 231 xenograft mouse model. Thus AP1-ELP-(KLAKLAK)2 polymer enhanced apoptotic and antitumor activity against IL-4R highly expressing tumor cells suggesting the clinical potential of our polymer. Citation Format: Sarangthem V. Devi, Yun Jae Kim, Young-Jin Lee, Kuen Hur, Byung-Heon Lee, Rang Woon Park. Multivalent targeting based delivery of therapeutic peptide using AP1-ELP carrier for effective cancer therapy. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4538. doi:10.1158/1538-7445.AM2015-4538