Article pubs.acs.org/bc
pH-Sensitive O6-Benzylguanosine Polymer Modified Magnetic Nanoparticles for Treatment of Glioblastomas Zachary R. Stephen,† Rachel N. Gebhart,‡ Mike Jeon,† Allison A. Blair,§ Richard G. Ellenbogen,∥,⊥ John R. Silber,∥ and Miqin Zhang*,†,∥ †
Department of Materials Science and Engineering, ‡Department of Chemistry, §Department of Biochemistry, ∥Department of Neurological Surgery, and ⊥Department of Radiology, University of Washington, Seattle, Washington 98195, United States S Supporting Information *
ABSTRACT: Nanoparticle-mediated delivery of chemotherapeutics has demonstrated potential in improving anticancer efficacy by increasing serum half-life and providing tissue specificity and controlled drug release to improve biodistribution of hydrophobic chemotherapeutics. However, suboptimal drug loading, particularly for solid core nanoparticles (NPs), remains a challenge that limits their clinical application. In this study we formulated a NP coated with a pH-sensitive polymer of O6-methylguanine-DNA methyltransferase (MGMT) inhibitor analog, dialdehyde modified O 6 -benzylguanosine (DABGS) to achieve high drug loading, and polyethylene glycol (PEG) to ameliorate water solubility and maintain NP stability. The base nanovector consists of an iron oxide core (9 nm) coated with hydrazide functionalized PEG (IOPH). DABGS and PEG-dihydrazide were polymerized on the iron oxide nanoparticle surface (IOPH-pBGS) through acid-labile hydrazone bonds utilizing a rapid, freeze−thaw catalysis approach. DABGS polymerization was confirmed by FTIR and quantitated by UV−vis spectroscopy. IOPH-pBGS demonstrated excellent drug loading of 33.4 ± 5.1% by weight while maintaining small size (36.5 ± 1.8 nm). Drug release was monitored at biologically relevant pHs and demonstrated pH dependent release with maximum release at pH 5.5 (intracellular conditions), and minimal release at physiological pH (7.4). IOPH-pBGS significantly suppressed activity of MGMT and potentiated Temozolomide (TMZ) toxicity in vitro, demonstrating potential as a new treatment option for glioblastomas (GBMs).
■
INTRODUCTION GBMs are highly aggressive, infiltrative brain tumors affecting 14 000 individuals a year in the United States and present many treatment challenges. 1 The tumor is afforded variable protection within the blood-brain barrier (BBB) and can develop chemoresistance due to efflux and upregulation of DNA repair factors.2 Even with aggressive treatment comprising surgery, chemotherapy, and radiation, mean survival is 12− 15 months,3,4 with a 5-year survival of
