Abstract 3703: Nanoparticle-induced targeted pro-apoptotic peptide in glioblastoma

Abstract

Abstract Glioblastomas multiforme (GBM) are the most common and lethal form of intracranial tumors. They account for approximately 70% of the 22,500 new cases of malignant primary brain tumors that are diagnosed in adults in the United States each year. Although relatively uncommon, malignant gliomas are associated with disproportionately high morbidity and mortality (median survival is only 12 to 15 months). Malignant gliomas are among the most vascular of human tumors. Tumor vasculature has proven to be particularly well suited as a site for receptor-based targeting. It expresses a multitude of molecules that are not expressed in the vessels of normal tissues. Our laboratory screens phage-displayed peptide libraries in vivo and ex vivo to discover specific targets in tumor vessels. One of the peptides, CGKRK (1) binds to the blood vessels in various kinds of tumors. Initial experiments showed that intravenously injected CGKRK peptide effectively homes to lentiviral (H-RasV12-sip53)-induced glioma in mice. We coupled the CGKRK peptide to the alpha-helical amphipathic peptide D[KLAKLAK]2, which is toxic to eukaryotic cells if it internalized into the cells (2). The chimeric peptide, when added to actively growing HUVEC or U87 glioma cells colocalized with mitochondria, whereas D[KLAKLAK]2 did not. Iron oxide nanoworms (NW) coated with the chimeric D[KLAKLAK]2-CGKRK peptide were 100-200-fold more toxic to the HUVEC and U87 cells than the free peptide in vitro and specifically accumulated in the blood vessels of glioma. Treatment of lentiviral induced glioma in mice with the D[KLAKLAK]2-CGKRK-PEG-NW inhibited tumor growth and showed a significant survival increase compared to control-treated mice. 1. Hoffman, J.A., et al. Progressive vascular changes in a transgenic mouse model of squamous cell carcinoma. Cancer Cell 4, 383-391 (2003). 2. Ellerby, H.M., et al. Anti-cancer activity of targeted pro-apoptotic peptides. Nat Med 5, 1032-1038 (1999). *These authors contributed equally to this work Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3703.