Controlled release of FGF-2 using fragmin/protamine microparticles and effect on neovascularization.
Water-insoluble fragmin/protamine microparticles of about 0.5-1 mum in diameter were prepared by simple mixing of low-molecular-weight heparin (fragmin) with protamine. We investigated the capability of these microparticles to immobilize fibroblast growth factor (FGF)-2, to protect FGF-2 against degradation, to enhance FGF-2 activity, and to facilitate controlled release of FGF-2. FGF-2 bound to the fragmin/protamine microparticles with high affinity (Kd = 2.08 x 10(-9) M) and the half-life of FGF-2-activity was prolonged substantially through binding of FGF-2 to the microparticles, by protection of FGF-2 from inactivation by heat and proteolysis. After subcutaneous injection into the back of mice, the fragmin/protamine microparticles underwent biodegradation and disappeared in about 2 weeks. A similar injection of FGF-2-containing microparticles resulted in significant neovascularization and fibrous tissue formation near the injection site after 1 week. These results indicate that controlled release of biologically active FGF-2 occurs through both slow diffusion and biodegradation of the microparticles, with subsequent induction of neovascularization. (c) 2008 Wiley Periodicals, Inc. J Biomed Mater Res, 2009.
Nakamura
Shingo
S
Department of Surgery, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama 359-8513, Japan.
Kanatani
Yasuhiro
Y
Kishimoto
Satoko
S
Nakamura
Shin-ichiro
S
Ohno
Chizuko
C
Horio
Takuya
T
Masanori
Fujita
F
Hattori
Hidemi
H
Tanaka
Yoshihiro
Y
Kiyosawa
Tomoharu
T
Maehara
Tadaaki
T
Ishihara
Masayuki
M
D000818:Animals; D001673:Biodegradation, Environmental; D017985:Dalteparin / Q000737:chemistry*; D004058:Diffusion; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems; D016222:Fibroblast Growth Factor 2 / Q000008:administration & dosage* / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D008297:Male; D051379:Mice; D008863:Microspheres; D009389:Neovascularization, Pathologic; D011479:Protamines / Q000378:metabolism*; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D013696:Temperature
D011479:Protamines; D016222:Fibroblast Growth Factor 2; D017985:Dalteparin