Abstract 1329: Intravenous delivery of Erlotinib-loaded PLA-PEG nanoparticles for treatment of GB

Abstract

Abstract Amplification, overexpression, and mutation of the epidermal growth factor receptor (EGFR) gene represent common genetic signature abnormalities (>50%) in primary glioblastomas (GBs) that arise de novo. Although activated EGFR signaling represents the most common genetic abnormality in GB, targeted therapeutics against EGFR, such as Erlotinib and Gefitinib, have found very limited clinical success mainly because of restricted access to the tumor cells behind the blood brain barrier. Nanoparticles, such as those composed of poly(lactic acid)-poly(glycolic acid) (PLA-PEG), may be capable of overcoming delivery barriers to expand the armamentarium of drugs useful against GB. PLA-PEG is one of only two polymer NP formulations in phase II clinical trial for intravenous administration (NCT01812746). In this study, we tested the ability of Erlotinib-loaded PLA-PEG nanoparticles to inhibit the EGFR signaling pathway in short-term cultures of GB patient derived xenograft (PDX) models. We also tested the ability of systemically administered PLA-PEG nanoparticles to deliver Erlotinib payload to intracranial GB PDX cells by pharmacokinetic (PK) analysis. Potency of Erlotinib-loaded PLA-PEG was determined in four PDX models (GBM6, GBM12, GBM39, and GBM59) with known EGFR and PTEN status using immunoblot analysis and CellTiterGlo® assay. Our results demonstrate that Erlotinib PLA-PEG inhibits EGFR signaling in all PDX models tested with potency equal to free Erlotininb (EC50 range 4.9 - 16.8 μM). Pharmacokinetic measurements were done in plasma and brain tissue samples (tumor-bearing hemisphere and contralateral hemisphere were analyzed separately) collected from intracranial GBM12 tumor bearing mice at 5 min, 1 hr, 6hr, and 24 hr after intravenous (IV) dose of free Erlotinib at 7.5 mg/Kg and Erlotininb PLA-PEG at 13.125 mg/Kg. PLA-PEG-mediated brain penetration (AUCplasm:AUCBrain) of Erlotinib is ∼7.5%. Using orthotopic PDX implants, perivascular/intratumoral penetration by PLA-PEG is being measured. Additional improvements in PLA-PEG to heighten uptake into brain, as well as tumor-specific targeting and enriched payload density will foster improved clinical utility of EGFR targeted therapies against GB. Supported by a grant from the Ben & Catherine Ivy Foundation. Citation Format: Lauren K. Hartman, Harshil D. Dhruv, Kyle T. Householder, Jeffrey E. Roth, Allison N. Schorzman, William Zamboni, Rachel Sirianni, Michael E. Berens. Intravenous delivery of Erlotinib-loaded PLA-PEG nanoparticles for treatment of GB. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1329.