Tissue inhibitor of matrix metalloproteinases-1 loaded poly(lactic-co-glycolic acid) nanoparticles for delivery across the blood-brain barrier

Int J Nanomedicine. 2014 Jan 20;9:575-88. doi: 10.2147/IJN.S54750. eCollection 2014.

Abstract

Aim: The aim of this study was to develop poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) for delivery of a protein - tissue inhibitor of matrix metalloproteinases 1 (TIMP-1) - across the blood-brain barrier (BBB) to inhibit deleterious matrix metalloproteinases (MMPs).

Materials and methods: The NPs were formulated by multiple-emulsion solvent-evaporation, and for enhancing BBB penetration, they were coated with polysorbate 80 (Ps80). We compared Ps80-coated and uncoated NPs for their toxicity, binding, and BBB penetration on primary rat brain capillary endothelial cell cultures and the rat brain endothelial 4 cell line. These studies were followed by in vivo studies for brain delivery of these NPs.

Results: Results showed that neither Ps80-coated nor uncoated NPs caused significant opening of the BBB, and essentially they were nontoxic. NPs without Ps80 coating had more binding to endothelial cells compared to Ps80-coated NPs. Penetration studies showed that TIMP-1 NPs + Ps80 had 11.21%± 1.35% penetration, whereas TIMP-1 alone and TIMP-1 NPs without Ps80 coating did not cross the endothelial monolayer. In vivo studies indicated BBB penetration of intravenously injected TIMP-1 NPs + Ps80.

Conclusion: The study demonstrated that Ps80 coating of NPs does not cause significant toxic effects to endothelial cells and that it can be used to enhance the delivery of protein across endothelial cell barriers, both in vitro and in vivo.

Keywords: BBB penetration; PLGA nanoparticles; RBCEC culture; brain delivery; drug delivery; protein delivery; sustained release.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood-Brain Barrier / drug effects
  • Blood-Brain Barrier / metabolism*
  • Cell Line
  • Cells, Cultured
  • Chemistry, Pharmaceutical
  • Delayed-Action Preparations
  • Drug Delivery Systems*
  • Endothelial Cells / drug effects
  • Endothelial Cells / metabolism
  • Lactic Acid / chemistry*
  • Nanomedicine
  • Nanoparticles / administration & dosage*
  • Nanoparticles / chemistry*
  • Nanoparticles / toxicity
  • Nanotechnology
  • Polyglycolic Acid / chemistry*
  • Polylactic Acid-Polyglycolic Acid Copolymer
  • Polysorbates / chemistry
  • Rats
  • Surface-Active Agents / chemistry
  • Tissue Inhibitor of Metalloproteinase-1 / administration & dosage*
  • Tissue Inhibitor of Metalloproteinase-1 / pharmacokinetics

Substances

  • Delayed-Action Preparations
  • Polysorbates
  • Surface-Active Agents
  • TIMP1 protein, rat
  • Tissue Inhibitor of Metalloproteinase-1
  • Polylactic Acid-Polyglycolic Acid Copolymer
  • Polyglycolic Acid
  • Lactic Acid