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Selective binding of C-6 OH sulfated hyaluronic acid to the angiogenic isoform of VEGF(165).
- Source :
-
Biomaterials [Biomaterials] 2016 Jan; Vol. 77, pp. 130-138. Date of Electronic Publication: 2015 Oct 30. - Publication Year :
- 2016
-
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 × 10(6) 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.<br /> (Copyright © 2015 Elsevier Ltd. All rights reserved.)
- Subjects :
- Amino Acid Sequence
Angiogenesis Inhibitors chemical synthesis
Angiogenesis Inhibitors pharmacology
Bevacizumab metabolism
Carbohydrate Conformation
Chondroitin Sulfates metabolism
Drug Evaluation, Preclinical
Human Umbilical Vein Endothelial Cells
Humans
Hyaluronic Acid chemical synthesis
Hyaluronic Acid metabolism
Hyaluronic Acid pharmacology
Kinetics
Molecular Sequence Data
Molecular Weight
Neovascularization, Physiologic drug effects
Protein Binding
Protein Structure, Tertiary
Recombinant Proteins metabolism
Substrate Specificity
Angiogenesis Inhibitors metabolism
Hyaluronic Acid analogs & derivatives
Vascular Endothelial Growth Factor A metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1878-5905
- Volume :
- 77
- Database :
- MEDLINE
- Journal :
- Biomaterials
- Publication Type :
- Academic Journal
- Accession number :
- 26588795
- Full Text :
- https://doi.org/10.1016/j.biomaterials.2015.10.074