Convection-enhanced delivery of methotrexate-loaded maghemite nanoparticles

Abstract

Enav Corem-Salkmon1, Zvi Ram2,3, Dianne Daniels3,4, Benny Perlstein1, David Last4, Sharona Salomon4, Gregory Tamar4, Ran Shneor4, David Guez4, Shlomo Margel1, Yael Mardor3,41The Institute of Nanotechnology and Advanced Materials, Department of Chemistry, Bar-Ilan University, Ramat-Gan, 2Department of Neurosurgery, Tel Aviv Medical Center, Tel Aviv, 3Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, 4Advanced Technology Center, Sheba Medical Center, Tel-Hashomer, IsraelAbstract: Convection-enhanced delivery (CED) is a novel approach for delivering drugs directly into brain tumors by intracranial infusion, enabling the distribution of high drug concentrations over large tissue volumes. This study was designed to present a method for binding methotrexate (MTX) to unique crystalline, highly ordered and superparamagnetic maghemite nanoparticles via human serum albumin (HSA) coating, optimized for CED treatments of gliomas. Naked nanoparticles and HSA- or polyethylene glycol (PEG)-coated nanoparticles with/without MTX were studied. In vitro results showed no toxicity and a similar cell-kill efficacy of the MTX-loaded particles via HSA coating to that of free MTX, while MTX-loaded particles via PEG coating showed low efficacy. In vivo, the PEG-coated nanoparticles provided the largest distributions in normal rat brain and long clearance times, but due to their low efficacy in vitro, were not considered optimal. The naked nanoparticles provided the smallest distributions and shortest clearance times. The HSA-coated nanoparticles (with/without MTX) provided good distributions and long clearance times (nearly 50% of the distribution volume remained in the brain 3 weeks post treatment). No MTX-related toxicity was noted. These results suggest that the formulation in which HSA was bound to our nanoparticles via a unique precipitation method, and MTX was bound covalently to the HSA, could enable efficient and stable drug loading with no apparent toxicity. The cell-kill efficacy of the bound MTX remained similar to that of free MTX, and the nanoparticles presented efficient distribution volumes and slow clearance times in vivo, suggesting that these particles are optimal for CED.Keywords: convection-enhanced delivery, nanoparticles, methotrexate, magnetic resonance imaging, rat brain