DDEL-03. ASSESSING THE DEPTH OF DRUG PENETRATION INTO BRAIN PARENCHYMA FROM LOCAL DRUG DELIVERY SYSTEMS IN AN ORTHOTOPIC HIGH GRADE GLIOMA ALLOGRAFT USING ORBITRAP-SECONDARY ION MASS SPECTROMETRY

Abstract

Abstract Local intracranial drug delivery for high-grade glioma has been developed over the last two decades with chemotherapeutic agents administered immediately adjuvant to neurosurgery to overcome poor blood brain barrier permeability. In addition to this, the incorporation of nanoparticles (NPs) into local drug delivery systems (DDS) can result in increased penetration of chemotherapeutics through brain parenchyma, transporting the drug further from the administration site than by drug molecule diffusion alone.Here we adopted two model local DDS containing NPs to compare the depth of penetration through brain parenchyma. Approach one consisted of a thermosensitive in situ assembling polymer matrix loaded with polymer-doxorubicin conjugated NPs which can line the resection cavity walls, while approach two consisted of drug-loaded (etoposide and olaparib) poly(lactic acid)-poly(ethylene glycol) polymeric NPs held within a bioadhesive pectin hydrogel and delivered via a spray device.We assessed the efficacy of both DDS at preventing recurrence of high-grade glioma in an orthotopic rat 9L gliosarcoma model following surgical resection. In addition to monitoring long-term survival, the effect of each DDS was measured histologically by H&E and by caspase-1 (inflammatory response) and ki67 (cell proliferation) immunostaining staining. Depth of drug penetration was evaluated on post-sacrificial sections using Orbitrap-Secondary Ion Mass Spectroscopy (OrbiSIMS) and fluorescent microscopy. In vivo data suggests that the delivery mechanism of the NPs affects the efficacy of the DDS, whereby long-term survival was observed in rats treated with the sprayed olaparib/etoposide NP formulation, relative to rats where olaparib/etoposide was simply pipetted into the resection cavity. OrbiSIMS confirmed the presence of doxorubicin, olaparib and etoposide in brain tissue. Our work encourages consideration of mass spectrometry modalities to complement in vivo efficacy studies, as an analytical tool to assess brain distribution of systemically administered drugs, or localised brain penetration of drugs released biomaterial-based DDS.