Poly aspartic acid peptide-linked PLGA based nanoscale particles: potential for bone-targeting drug delivery applications

Int J Pharm. 2014 Nov 20;475(1-2):547-57. doi: 10.1016/j.ijpharm.2014.08.067. Epub 2014 Sep 4.

Abstract

Delivering drugs specifically to bone tissue is very challenging due to the architecture and structure of bone tissue. Poly(lactic-co-glycolic acid) (PLGA)-based nanoparticles (NPs) hold great promise for the delivery of therapeutics to bone tissue. The goal of the present research was to formulate a PLGA-based NP drug delivery system for bone tissue exclusively. Since poly-aspartic acids (poly-Asp) peptide sequence has been shown to bind to hydroxyapatite (HA), and has been suggested as a molecular tool for bone-targeting applications, we fabricated PLGA-based NPs linked with poly-Asp peptide sequence. Nanoparticles made of methoxy - poly(ethylene glycol) (PEG)-PLGA and maleimide-PEG-PLGA were prepared using a water-in-oil-in-water double emulsion and solvent evaporation method. Fluorescein isothiocyanate (FITC)-tagged poly-Asp peptide was conjugated to the surface of the nanoparticles via the alkylation reaction between the sulfhydryl groups at the N-terminal of the peptide and the CC double bond of maleimide at one end of the polymer chain to form thioether bonds. The conjugation of FITC-tagged poly-Asp peptide to PLGA NPs was confirmed by NMR analysis and fluorescent microscopy. The developed nanoparticle system is highly aqueous dispersible with an average particle size of ∼80 nm. In vitro binding analyses demonstrated that FITC-poly-Asp NPs were able to bind to HA gel as well as to mineralized matrices produced by human mesenchymal stem cells and mouse bone marrow stromal cells. Using a confocal microscopy technique, an ex vivo binding study of mouse major organ ground sections revealed that the FITC-poly-Asp NPs were able to bind specifically to the bone tissue. In addition, proliferation studies indicated that our FITC-poly-Asp NPs did not induce cytotoxicity to human osteoblast-like MG63 cell lines. Altogether, these promising results indicated that this nanoscale targeting system was able to bind to bone tissue specifically and might have a great potential for bone disease therapy in clinical applications.

Keywords: Bone diseases; Nanoparticles; Peptides; Targeted drug delivery.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone and Bones / metabolism*
  • Cell Line
  • Cell Proliferation
  • Cell Survival
  • Chemistry, Pharmaceutical / methods
  • Drug Carriers / chemistry*
  • Durapatite / metabolism
  • Fluorescein-5-isothiocyanate
  • Humans
  • Lactic Acid / chemistry*
  • Mice
  • Nanoparticles / chemistry*
  • Peptides / chemistry*
  • Polyglycolic Acid / chemistry*
  • Polylactic Acid-Polyglycolic Acid Copolymer
  • Stromal Cells / metabolism
  • Surface Properties

Substances

  • Drug Carriers
  • Peptides
  • Polylactic Acid-Polyglycolic Acid Copolymer
  • Polyglycolic Acid
  • polyaspartate
  • Lactic Acid
  • Durapatite
  • Fluorescein-5-isothiocyanate