DDEL-25. Increasing the Potency of Chemotherapy Particles for GBM Treatment by Mediating Trafficking to Autolysosomes

Abstract Patients presenting with glioblastoma (GBM) face a grim prognosis with a median survival rate of less than two years. Encapsuling chemotherapeutics within particles enhances drug accumulation within the tumor. However, drug release from the particle, and subcellular trafficking to the organelle required for tumor eradication remains challenging. To overcome these obstacles, our group identified a peptide that internalizes into cells relative to the autophagy levels within the cell. Once internalized, the peptide mediates subcellular trafficking of particles to autolysosomes which break down the particles and deposit the contents directly into the cytosol. To identify a peptide that mediates trafficking of particles to autolysosomes, we used phage display. Each round, phage were incubated with U87 GBM cells, and then the microsomal fraction of the U87 cells was harvested to enrich for phage displayed peptides that mediate trafficking to autolysosomes. The lead peptide mediates particle trafficking from extracellular space into autolysosomes. The peptide internalizes into cancerous, normal, normal cells infected with pathogens relative to the amount of autophagy, as measured by LC3-II levels. Inducing autophagy by starvation, pathogen infection, pharmaceutic treatments, or malignancy stimulates peptide uptake. Biodistribution studies demonstrate significant accumulation of peptide labelled particles within the tumor region of mice bearing syngeneic, intracranial GBM that peaks at 48 hours post administration. Peptide targeted doxorubicin loaded liposomes imparted a significant survival benefit in mice bearing PDX GBM orthotopic tumors compared to controls (p<0.05 using log-rank tests). Finally, we identified the receptor for the peptide using mass spectrometry and siRNA methods. In summation, we identified a novel peptide that accumulates in all mammalian cells relative to the level of autophagy a cell is undergoing. The peptide was optimized and the binding ligand identified. Peptide displaying liposomes accumulate within the tumor regions of mice bearing intracranial GBM, and deliver chemotherapy encapsulated within particles directly into the cytosol of cancer cells with elevated levels of autophagy.