PO46NANOPARTICLE-ASSOCIATED CELL PENETRATING AND CYTOTOXIC PEPTIDES AS A NOVEL THERAPEUTIC STRATEGY FOR MALIGNANT GLIOMA

Abstract

INTRODUCTION: Local neurosurgically-applied drug-delivery systems offer an opportunity to target glioblastoma (GBM) residual disease, but consideration must be given to the uptake of delivered agents once diffused from a drug-delivery depot. We assess the glycosaminoglycan-binding enhanced transduction of nanoparticles coated with genetically-engineered peptides, as a direct corollary to biomaterial-based localised drug-delivery systems. METHOD: GBM cells were transduced with biocompatible iron oxide magnetic nanoparticles (dMNP) coated with membrane docking (P21) and cell penetrating (8R) peptides. Protein transduction efficiency was determined by cytochemical staining and metabolic assays. To test the efficacy of the cytotoxic peptide SHEPHERDIN (SHEP), which disrupts the interaction of Survivin with HSP 90, GBM cells were exposed to acute doses of dMNP-P21-8R-SHEP and effects on metabolism measured. RESULTS: Nuclear and cytoplasmic protein transduction of dMNP-8R-P21 was evident in 100% of adult and paediatric GBM cells after 3h exposure, whereas after 16h, only 25% of uncoated nanoparticles traverse the cellular membrane by direct translocation and/or endocytosis. Protein-mediated transduction of dMNP-P21-8R-SHEP results in dose-dependent proliferation impairment of adult and paediatric GBM cells (IC50 25 µM and 20 µM respectively). CONCLUSION: Protein-mediated cellular transduction via membrane docking and cell penetrating peptides has the potential to deliver anti-cancer cargos to brain tumours and diversifies nanoparticle functionality. Early findings characterising SHEP-mediated GBM viability loss and controlled release of dMNP-P21-8R-SHEP from a polymeric microparticle drug-delivery matrix will be discussed.