title: Anti-Flt1 peptide - hyaluronate conjugate for the treatment of retinal neovascularization and diabetic retinopathy.
abstract: Anti-angiogenic therapeutics has been investigated extensively for the treatment of retinal and choroidal vascular diseases, and diabetic retinopathy. Anti-Flt1 peptide of GNQWFI is an antagonistic peptide for vascular endothelial growth factor receptor 1 (VEGFR1 or Flt1) inhibiting VEGFR1-mediated endothelial cell migration and tube formation. In this work, anti-Flt1 peptide (GGNQWFI) was chemically conjugated to tetra-n-butyl ammonium modified hyaluronate (HA-TBA) via amide bond formation in dimethyl sulfoxide (DMSO) using benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP). The resulting HA - GGNQWFI conjugate self-assembled to form micelle-like nanoparticles in aqueous solution, as confirmed and characterized by transmission electron microscopy (TEM). According to in vitro biological activity tests, HA - GGNQWFI conjugate exhibited a dose-dependent inhibition effect on the binding of Flt1-Fc to VEGF(165) coated on the well. Furthermore, anti-Flt1 peptide - HA conjugate effectively inhibited retinal choroidal neovascularization (CNV) in laser induced CNV model rats. The retinal vascular permeability and the deformation of retinal vascular structure were also significantly reduced in diabetic retinopathy model rats after treatment with anti-Flt1 peptide - HA conjugate. Pharmacokinetic analysis confirmed the increased mean residence time of anti-Flt1 peptide after conjugation to HA longer than 2 weeks.
authors.affiliation: Department of Materials Science and Engineering, Pohang University of Science and Technology (POSTECH), San 31, Hyoja-dong, Nam-gu, Pohang, Kyungbuk 790-784, Republic of Korea.
authors.forename: Eun Ju
authors.initials: EJ
authors.lastname: Oh
authors.forename: Jun-Sub
authors.initials: JS
authors.lastname: Choi
authors.forename: Hyemin
authors.initials: H
authors.lastname: Kim
authors.forename: Choun-Ki
authors.initials: CK
authors.lastname: Joo
authors.forename: Sei Kwang
authors.initials: SK
authors.lastname: Hahn
mesh_terms: D000818:Animals; D003930:Diabetic Retinopathy / Q000188:drug therapy*; D006820:Hyaluronic Acid / Q000737:chemistry*; D008297:Male; D010455:Peptides / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015861:Retinal Neovascularization / Q000188:drug therapy*; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000037:antagonists & inhibitors*
chemical_list: D010455:Peptides; D006820:Hyaluronic Acid; D040281:Vascular Endothelial Growth Factor Receptor-1