Fragmin/protamine microparticles to adsorb and protect HGF and to function as local HGF carriers in vivo

Satoko Kishimoto, Masayuki Ishihara, Shingo Nakamura, Masanori Fujita, Megumi Takikawa, Yuki Sumi, Tomoharu Kiyosawa, Toshinori Sato, Yasuhiro Kanatani

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Abstract

The clinical efficacy of hepatocyte growth factor (HGF) in tissue repair can be greatly enhanced by high affinity, biocompatible drug carriers that maintain the bioactivity and regulate release at the target site. We produced 0.5-3.0 μm fragmin (low molecular weight heparin)/protamine microparticles (F/P MPs) as carriers for the controlled release of HGF. F/P MPs immobilized more than 3 μg of HGF per mg of MPs and gradually released the absorbed HGF into the medium with a half-release time of approximately 5 days. Compared with HGF alone, HGF-containing F/P MPs substantially enhanced the mitogenic effect of HGF on cultured human microvascular endothelial cells, by prolonging the biological half-life, and its conjugation to F/P MPs protected HGF from heat and proteolytic inactivation. F/P MPs disappeared 8 days after subcutaneous injection in mice, suggesting that they are rapidly biodegraded. Furthermore, the number of large (diameter ≥200 μm or containing ≥100 erythrocytes) and medium (diameter 20-200 μm or containing 10-100 erythrocytes) lumen capillaries 8 days after injection of HGF-containing F/P MPs was significantly higher than that after injection of HGF or F/P MPs alone. Furthermore, the number of small (diameter ≤20 μm or containing 1-10 erythrocytes) lumen capillaries was significantly higher 4 days after injection of HGF-containing F/P MPs. This increased angiogenic activity of HGF in vivo is probably due to both sustained local release and protection against biodegradation by the F/P MPs. Thus, F/P MPs may be useful and safe HGF carriers that facilitate cell proliferation and vascularization at sites of tissue damage.

Original languageEnglish
Pages (from-to)4763-4770
Number of pages8
JournalActa Biomaterialia
Volume9
Issue number1
DOIs
Publication statusPublished - 2013 Jan

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Keywords

  • Angiogenesis
  • Drug carrier
  • Hepatocyte growth factor
  • Low molecular weight heparin (fragmin)/protamine microparticles

ASJC Scopus subject areas

  • Biomaterials
  • Biomedical Engineering
  • Biotechnology
  • Biochemistry
  • Molecular Biology

Cite this

Kishimoto, S., Ishihara, M., Nakamura, S., Fujita, M., Takikawa, M., Sumi, Y., Kiyosawa, T., Sato, T., & Kanatani, Y. (2013). Fragmin/protamine microparticles to adsorb and protect HGF and to function as local HGF carriers in vivo. Acta Biomaterialia, 9(1), 4763-4770. https://doi.org/10.1016/j.actbio.2012.08.003