Biodistribution of Fracture-Targeted GSK3β Inhibitor-Loaded Micelles for Improved Fracture Healing

Stewart A. Low, Chris V. Galliford, Jiyuan Yang, Philip S. Low, Jindřich Kopeček

Research output: Contribution to journalArticle

16 Scopus citations

Abstract

Bone fractures constitute a major cause of morbidity and mortality especially in the elderly. Complications associated with osteoporosis drugs and the age of the patient slow bone turnover and render such fractures difficult to heal. Increasing the speed of fracture repair by administration of a fracture-targeted bone anabolic agent could find considerable application. Aspartic acid oligopeptides are negatively charged molecules at physiological pH that adsorb to hydroxyapatite, the mineral portion of bone. This general adsorption is the strongest where bone turnover is highest or where hydroxyapatite is freshly exposed. Importantly, both of these conditions are prominent at fracture sites. GSK3β inhibitors are potent anabolic agents that can promote tissue repair when concentrated in a damaged tissue. Unfortunately, they can also cause significant toxicity when administered systemically and are furthermore difficult to deliver due to their strong hydrophobicity. In this paper, we solve both problems by conjugating the hydrophobic GSK3β inhibitor to a hydrophilic aspartic acid octapeptide using a hydrolyzable bond, thereby generating a bone fracture-targeted water-soluble form of the drug. The resulting amphiphile is shown to assemble into micelles, extending its circulation time while maintaining its fracture-targeting abilities. For measurement of pharmacokinetics, an 125I was introduced at the location of the bromine in the GSK3β inhibitor to minimize any structural differences. Biodistribution studies demonstrate a greater than 4-fold increase in fracture accumulation over healthy bone.

Original languageEnglish (US)
Pages (from-to)3145-3153
Number of pages9
JournalBiomacromolecules
Volume16
Issue number10
DOIs
StatePublished - Oct 12 2015

ASJC Scopus subject areas

  • Bioengineering
  • Biomaterials
  • Polymers and Plastics
  • Materials Chemistry

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