Abstract 1343: P32-targeting TT1 peptide delivers nanoparticles to intracranial glioblastomas

Abstract

Abstract Targeted delivery of cancer therapeutics using affinity ligands can dramatically improve antitumor efficacy. Over the years a number of homing peptides that upon systemic injection accumulate in solid tumors have been identified by in vivo peptide phage display. In a quest to find homing peptides optimally suited for drug delivery to high-grade gliomas, our laboratories are using advanced mouse models of glioblastoma (GBM) to systematically audit known tumor-homing peptides and to perform new in vivo screens using peptide phage libraries. P32 is a mitochondrial chaperone that is aberrantly expressed on the cell surface in activated malignant and stromal cells in tumors. P32 is a receptor for widely used LypP-1 peptide and for recently identified TT1 peptide. Here we show that iron oxide nanoworms (IONW) functionalized with linear TT1 peptide (CKRGARST) strongly home to intracranial GBMs grafted in immune deficient mice. IONW are paramagnetic nanoparticles that are PEGylated to extend blood half-life, and have, because of their elongated shape, more effective targeting properties than spherical nanoparticles. Five hours after intravenous injection of IONW (7.5 mg/kg), macroscopic fluorescence imaging demonstrated robust homing of TT1-IONW in GBMs of murine origin (WT GBM and VEGF KO GBM from the G. Berger lab) and in a patient-derived glioma model (P13 model from the Bjerkvig lab). Confocal microscopy confirmed the presence of TT1 but not control IONW in gliomas, with TT1-IONW signal showing partial overlap with blood- and lymphatic vessel markers (CD31 and LYVE-1) in WT GBM and P13 gliomas, whereas lower level of colocalization with these markers was detected for mouse GBM not expressing VEGF. In addition, moderate colocalization between TT1-IONW and the macrophage marker CD11b was detected in the P13 tumors. Detailed phenotyping and functional characterization of TT1-positive macrophages is ongoing. Our data suggest that TT1 peptide has potential applications as a glioma-targeting vehicle. Currently, we are evaluating TT1-targeted IONWs as a contrast agent for glioma MRI and as carriers for cytotoxic compounds. Citation Format: Pille Säälik, Hedi Hunt, Allan Tobi, Anne-Mari Anton Willmore, Kadri Toome, Shweta Sharma, Ramana Kotamraju, Gabriele Bergers, Rolf Bjerkvig, Erkki Ruoslahti, Tambet Teesalu, Tambet Teesalu. P32-targeting TT1 peptide delivers nanoparticles to intracranial glioblastomas. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1343.