Selective binding of C-6 OH sulfated hyaluronic acid to the angiogenic isoform of VEGF165

Dong-Kwon Lim, Ryan G. Wylie, Robert Langer, Daniel S. Kohane

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

Vascular endothelial growth factor 165 (VEGF165) is an important extracellular protein involved in pathological angiogenesis in diseases such as cancer, wet age-related macular degeneration (wet-AMD) and retinitis pigmentosa. VEGF165 exists in two different isoforms: the angiogenic VEGF165a, and the anti-angiogenic VEGF165b. In some angiogenic diseases the proportion of VEGF165b may be equal to or higher than that of VEGF165a. Therefore, developing therapeutics that inhibit VEGF165a and not VEGF165b may result in greater anti-angiogenic activity and therapeutic benefit. To this end, we report the selective binding properties of sulfated hyaluronic acid (s-HA). Selective biopolymers offer several advantages over antibodies or aptamers including cost effective and simple synthesis, and the ability to make nanoparticles or hydrogels for drug delivery applications or VEGF165a sequestration. Limiting sulfation to the C-6 hydroxyl (C-6 OH) in the N-acetyl-glucosamine repeat unit of hyaluronic acid (HA) resulted in a polymer with strong affinity for VEGF165a but not VEGF165b. Increased sulfation beyond the C-6 OH (i.e. greater than 1 sulfate group per HA repeat unit) resulted in s-HA polymers that bound both VEGF165a and VEGF165b. The C-6 OH sulfated HA (Mw 150 kDa) showed strong binding properties to VEGF165a with a fast association rate constant (Ka; 2.8 × 106 M-1 s-1), slow dissociation rate constant (Kd; 2.8 × 10-3 s-1) and strong equilibrium binding constant (KD; ~1.0 nM)), which is comparable to the non-selective VEGF165 binding properties of the commercialized therapeutic anti-VEGF antibody (Avastin®). The C-6 OH sulfated HA also inhibited human umbilical vein endothelial cell (HUVEC) survival and proliferation and human dermal microvascular endothelial cell (HMVEC) tube formation. These results demonstrate that the semi-synthetic natural polymer, C-6 OH sulfated HA, may be a promising biomaterial for the treatment of angiogenesis-related disease.

Original languageEnglish
Pages (from-to)130-138
Number of pages9
JournalBiomaterials
Volume77
DOIs
Publication statusPublished - 2016 Jan 1

Fingerprint

Hyaluronic acid
Hyaluronic Acid
Protein Isoforms
Polymers
Pathologic Neovascularization
Endothelial cells
Biopolymers
Hydrogels
Retinitis Pigmentosa
Glucosamine
Antibodies
Human Umbilical Vein Endothelial Cells
Macular Degeneration
Biocompatible Materials
Rate constants
Hydroxyl Radical
Nanoparticles
Vascular Endothelial Growth Factor A
Sulfates
Anti-Idiotypic Antibodies

Keywords

  • Angiogenesis
  • Selective binding property
  • Sulfated sodium hyaluronate
  • Vascular endothelial growth factor 165
  • VEGF
  • VEGF

ASJC Scopus subject areas

  • Bioengineering
  • Ceramics and Composites
  • Biophysics
  • Biomaterials
  • Mechanics of Materials

Cite this

Selective binding of C-6 OH sulfated hyaluronic acid to the angiogenic isoform of VEGF165. / Lim, Dong-Kwon; Wylie, Ryan G.; Langer, Robert; Kohane, Daniel S.

In: Biomaterials, Vol. 77, 01.01.2016, p. 130-138.

Research output: Contribution to journalArticle

Lim, Dong-Kwon ; Wylie, Ryan G. ; Langer, Robert ; Kohane, Daniel S. / Selective binding of C-6 OH sulfated hyaluronic acid to the angiogenic isoform of VEGF165. In: Biomaterials. 2016 ; Vol. 77. pp. 130-138.
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AB - Vascular endothelial growth factor 165 (VEGF165) is an important extracellular protein involved in pathological angiogenesis in diseases such as cancer, wet age-related macular degeneration (wet-AMD) and retinitis pigmentosa. VEGF165 exists in two different isoforms: the angiogenic VEGF165a, and the anti-angiogenic VEGF165b. In some angiogenic diseases the proportion of VEGF165b may be equal to or higher than that of VEGF165a. Therefore, developing therapeutics that inhibit VEGF165a and not VEGF165b may result in greater anti-angiogenic activity and therapeutic benefit. To this end, we report the selective binding properties of sulfated hyaluronic acid (s-HA). Selective biopolymers offer several advantages over antibodies or aptamers including cost effective and simple synthesis, and the ability to make nanoparticles or hydrogels for drug delivery applications or VEGF165a sequestration. Limiting sulfation to the C-6 hydroxyl (C-6 OH) in the N-acetyl-glucosamine repeat unit of hyaluronic acid (HA) resulted in a polymer with strong affinity for VEGF165a but not VEGF165b. Increased sulfation beyond the C-6 OH (i.e. greater than 1 sulfate group per HA repeat unit) resulted in s-HA polymers that bound both VEGF165a and VEGF165b. The C-6 OH sulfated HA (Mw 150 kDa) showed strong binding properties to VEGF165a with a fast association rate constant (Ka; 2.8 × 106 M-1 s-1), slow dissociation rate constant (Kd; 2.8 × 10-3 s-1) and strong equilibrium binding constant (KD; ~1.0 nM)), which is comparable to the non-selective VEGF165 binding properties of the commercialized therapeutic anti-VEGF antibody (Avastin®). The C-6 OH sulfated HA also inhibited human umbilical vein endothelial cell (HUVEC) survival and proliferation and human dermal microvascular endothelial cell (HMVEC) tube formation. These results demonstrate that the semi-synthetic natural polymer, C-6 OH sulfated HA, may be a promising biomaterial for the treatment of angiogenesis-related disease.

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