ATPS-78: PERSONALIZED CHEMOTHERAPY: TREATING BRAIN CANCERS WITH TARGETED NANOSYRINGES

The ability of targeted, epitope-specific, drug laden nanosyringes to raise chemotherapeutic levels within cancer cells, but not in non-targeted tissues is a promising avenue for cancer therapy. We have developed a nanosyringe system derived from single wall carbon nanotubes capable of carrying a wide range of drugs/dyes, and these constructs are targeted toward the surface of cancer cells via binding to specific, upregulated, tyrosine kinase receptors. As a technology demonstrator we have focused on a nanosyringe designed to bind to epidermal growth factor receptor EGFR. Targeting of the nanosyringe is achieved by the covalent linkage of multiple EGFR-specific binding peptides to the syringes' outer surface. The lipophilic and hydrophobic core of the nanosyringe is loaded with a wide range of hydrophobic compounds, which only leave the syringe when the construct binds to cell specific antigens and makes contact with the lipophilic and hydrophobic environment of the cell membrane. We can deliver large amounts of hydrophobic chemotherapeutic drugs or fluorescent probes to cancers cells expressing EGFR in vitro and in vivo. Binding of EGFR-targeted nanosyringe to EGFR in living cells causes EGFR homo/heterodimerization and receptor autophosphorylation at signaling residue T678. The phosphorylated receptor recruits adapter proteins inducing the formation of clathrin coated pits and the subsequent internalization of both the receptor and the nanosyringe. Using EGFR-targeted nanosyringes loaded with Nile Red fluorophore, we can rapidly transfer dye into gliomal cells, and both nanosyringe binding and dye transfer is competitive with EGF. Flank and intracranial tumor models of nude mice with gliomal U87-EGFR xenografts show uptake of Nile Red, delivered by nanosyringe, and dye transfer to non-target tissues is below detection thresholds. When loaded with chemotherapeutic drugs, and also with xenobiotic drug transport inhibitors, we can successfully treat a range of cancers, in flank and intracranial tumor models.