SCDT-15. DRUG-LOADED AND EGFR-TARGETED NANO-CONSTRUCTS SUCCESSFULLY TREAT INTRACRANIAL GLIOMA IN MOUSE MODELS

摘要

We have developed a peptidyl-targeted nanovector system, the nanosyringe, capable of transferring large amounts of hydrophobic dyes/drugs into cells bearing a targeted surface epitope, in vitro and in vivo. The nanovector is made from a hydrophobic, oxidized graphene core, with polyethylene glycol (PEG) tendrils attached via amide bonds. This untargeted nanovector is both water soluble and has a large internal volume that can be filled with hydrophobic drugs/dyes. Targeting the nanovectors toward specific epitopes is achieved by covalently linking targeting peptides to the PEG terminals, using peptides selected from phage-display libraries. The nanosyringe interior is readily loaded with hydrophobic drugs/dyes and when the GE11 peptide is attached, these nanosyringes are taken up by EGFR-expressing cells along with the nanosyringe payload. In our in vitro and in vivo studies we demonstrate that binding of nanosyringe activates EGFR, which in turn initiates binding/internalization and transfer of payload into the cells. Nanosyringe binding to EGFR causes activation of the clathrin coated-pit endosomal pathway, internalizing the nanosyringes within endosomes. When drugs such as doxorubicin are loaded into nanosyringes, we observe initial transfer into cellular plasma/endosomal membranes, followed by diffusion into the cytosol, then into DNA.In intracranial mouse models of glioma, when drugs are loaded into EGFR-targeted nanosyringes, we observe both enhanced efficacy of chemotherapeutics and lower off-target toxicity.In GBM, highly effective chemotherapeutics such as Vinblastine and Doxorubicin are seldom used clinically because of their off-target toxicity. When comparing native and nanosyringe-loaded chemotherapy in an aggressive intracranial glioma mouse model we observe a huge enhancement (>7-fold) in animal survival, and far lower off-target toxicity. 38% of vinblastine and 50% of doxorubicin treated animals out survived the empty vector controls by more than a year.