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

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• 作者：Dong-Kwon Lim^a ; ^d ; ¹ ; Ryan G. Wylie^b ; ^d ; ¹ ; Robert Langer^c ; Daniel S. Kohane^d ; ^{daniel.kohane@childrens.harvard.edu" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Vascular endothelial growth factor 165 ; VEGF165a ; VEGF165b ; Angiogenesis ; Sulfated sodium hyaluronate ; Selective binding property
• 刊名：Biomaterials
• 出版年：2016
• 出版时间：January 2016
• 年：2016
• 卷：77
• 期：Complete
• 页码：130-138
• 全文大小：1381 K

文摘

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 VEGF_165a, and the anti-angiogenic VEGF_165b. In some angiogenic diseases the proportion of VEGF_165b may be equal to or higher than that of VEGF_165a. Therefore, developing therapeutics that inhibit VEGF_165a and not VEGF_165b 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 VEGF_165a 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 VEGF_165a but not VEGF_165b. 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 VEGF_165a and VEGF_165b. The C-6 OH sulfated HA (Mw 150 kDa) showed strong binding properties to VEGF_165a with a fast association rate constant (K_a; 2.8 × 10⁶ M⁻¹ s⁻¹), slow dissociation rate constant (K_d; 2.8 × 10⁻³ s⁻¹) and strong equilibrium binding constant (K_D; ∼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.