Abstract LB-95: Construction and application of elastin-like polypeptide containing IL-4 receptor targeting peptide.

Abstract

Abstract Cancer cells express a number of cell surface and matrix proteins that mediate tumor growth, migration, invasion, and metastasis. Screening for ligands that specifically target these molecules represents an excellent cancer therapy strategy. AP1 is a recently discovered peptide, homing onto atherosclerotic plaques and breast tumor tissues through selective binding to the interleukin 4 receptor (IL-4R). IL-4Rs are highly expressed in a variety of human tumors and it has been reported that IL-4/IL-4R interactions amplify the expression of some anti-apoptotic proteins thereby preventing drug-induced cancer cell death. Thus, targeting the IL-4R could possibly increase the therapeutic efficacy of anticancer drugs. Even though AP1 peptide possesses high target specificity and efficient tumor-homing, it has limitation due to easy elimination from the circulation and short half-life. To improve the binding affinity of AP1 and its avidity towards the IL-4R as well as its half-life, we incorporated multiple AP1 peptides into the elastin-like polypeptides (ELPs). Tandem repeats of ELP polymers containing AP1 peptide (AP1-ELPs) were prepared by using recursive directional ligation (RDL) method. The fluorescence-labeled A6V72, an AP1-ELP containing six AP1 units displayed superior binding ability to the IL-4R expressing cancer cell lines, H226 and MDA-MB-231. Surface plasmon resonance analysis showed that multivalent presentation of the targeting ligand AP1 in the ELP polymer backbone increased binding affinity to IL-4R approximately ~10, 000-fold compared to the free AP1 peptide, which is important for tumor targeting approach. The binding of AP1-ELPs was remarkably reduced when IL-4Rs were blocked with antibody against IL-4 receptor. Confocal microscopic imaging revealed the increased accumulation and uptake of A6V72 than V84 control ELP by H226 cells. Furthermore, the Cy5.5-labeled AP1-ELP showed excellent homing and longer retention in xenografted tumor tissues in mouse model. Immunohistological analysis of excised tumor tissues further verified the targeting of AP1-ELP to tumor. The present results imply that the AP1-ELPs can serve as novel carriers for effective delivery of therapeutic drugs to tumors. Citation Format: Sarangthem Vijaya Devi, Rang-Woon Park. Construction and application of elastin-like polypeptide containing IL-4 receptor targeting peptide. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-95. doi:10.1158/1538-7445.AM2013-LB-95