Convection-enhanced delivery of methotrexate-loaded maghemite nanoparticles

Int J Nanomedicine. 2011;6:1595-602. doi: 10.2147/IJN.S23025. Epub 2011 Aug 3.

Abstract

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; magnetic resonance imaging; methotrexate; nanoparticles; rat brain.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain Chemistry
  • Cell Death / drug effects
  • Cell Line, Tumor
  • Convection
  • Drug Delivery Systems / methods*
  • Ferric Compounds / administration & dosage*
  • Ferric Compounds / chemistry
  • Humans
  • Magnetic Resonance Imaging / methods
  • Male
  • Metal Nanoparticles / administration & dosage*
  • Metal Nanoparticles / chemistry
  • Methotrexate / administration & dosage*
  • Methotrexate / pharmacokinetics
  • Polyethylene Glycols / administration & dosage
  • Polyethylene Glycols / pharmacokinetics
  • Rats
  • Rats, Sprague-Dawley
  • Serum Albumin / administration & dosage
  • Serum Albumin / pharmacokinetics
  • Tissue Distribution

Substances

  • Ferric Compounds
  • Serum Albumin
  • ferric oxide
  • Polyethylene Glycols
  • Methotrexate