EMAIL THIS PAGE TO A FRIEND

Biomacromolecules

Serum-dependence of affinity-mediated VEGF release from biomimetic microspheres.


PMID 24773176

Abstract

Vascular endothelial growth factor (VEGF) activity is highly regulated via sequestering within the ECM and cell-demanded proteolysis to release the sequestered VEGF. Numerous studies have demonstrated that VEGF activity mediates cellular events leading to angiogenesis and capillary formation in vivo. This has motivated the study of biomaterials to sustain VEGF release, and in many cases, the materials are inspired by the structure and function of the native ECM. However, there remains a need for materials that can bind to VEGF with high specificity, as the in vivo environment is rich in a variety of growth factors (GFs) and GF-binding moieties. Here we describe a strategy to control VEGF release using hydrogel microspheres with tethered peptides derived from VEGF receptor 2 (VEGFR2). Using biomaterials covalently modified with varying concentrations of two distinct VEGFR2-derived peptides with varying serum stability, we analyzed both biomaterial and environmental variables that influence VEGF release and activity. The presence of tethered VEGF-binding peptides (VBPs) resulted in significantly extended VEGF release relative to control conditions, and the resulting released VEGF significantly increased the expansion of human umbilical vein endothelial cells in culture. VEGF release rates were also strongly influenced by the concentration of serum. The presence of Feline McDonough Sarcoma-like tyrosine kinase 1 (sFlt-1), a serum-borne receptor fragment derived from VEGF receptor 1, increased VEGF release rates, although sFlt-1 was not sufficient to recapitulate the release profile of VEGF in serum. Further, the influence of serum on VEGF release was not due to protease activity or nonspecific VEGF interactions in the presence of serum-borne heparin. VEGF release kinetics correlated well with a generalizable mathematical model describing affinity-mediated release of VEGF from hydrogel microspheres in defined conditions. Modeling results suggest a potential mechanism whereby competition between VEGF and multiple VEGF-binding serum proteins including sFlt-1, soluble kinase insert domain receptor (sKDR), and α2-macroglobulin (α2-M) likely influenced VEGF release from microspheres. The materials and mathematical model described in this approach may be useful in a range of applications in which sustained, biologically active GF release of a specific GF is desirable.

Related Materials

Product #

Image

Description

Molecular Formula

Add to Cart

107700
4-(Dimethylamino)pyridine, ReagentPlus®, ≥99%
C7H10N2
39405
4-(Dimethylamino)pyridine, purum, ≥98.0% (NT)
C7H10N2
714844
4-(Dimethylamino)pyridine solution, 0.5 M in THF
C7H10N2
714720
4-(Dimethylamino)pyridine solution, 0.5 M in ethyl acetate
C7H10N2
700169
4-(Dimethylamino)pyridine, ChemDose tablets, Loading: 0.04 mmol tablet.
C7H10N2
379115
DCC, 1.0 M in methylene chloride
C13H22N2
36650
DCC, puriss., ≥99.0% (GC)
C13H22N2
D80002
DCC, 99%
C13H22N2
66742
Dichloromethane, Selectophore, ≥99.5%
CH2Cl2
02575
Dichloromethane, analytical standard
CH2Cl2
633267
Dicyclohexylcarbodiimide solution, 60 wt. % in xylenes
C13H22N2
M1550000
Methylene chloride, European Pharmacopoeia (EP) Reference Standard
CH2Cl2
PHR1557
Methylene Chloride, Pharmaceutical Secondary Standard; Certified Reference Material
CH2Cl2
184527
Pyridine, spectrophotometric grade, ≥99%
C5H5N
02486
Pyridine, analytical standard
C5H5N
W296600
Pyridine, ≥99%
C5H5N
24-6510
Pyridine, SAJ first grade, ≥99.0%
C5H5N
PHR1558
Pyridine, Pharmaceutical Secondary Standard; Certified Reference Material
C5H5N
85886
Streptomycin solution, ~1 mg/mL in 1 mM EDTA, analytical standard
C21H39N7O12 · 1.5H2SO4
S1400000
Streptomycin sulfate, European Pharmacopoeia (EP) Reference Standard
C21H39N7O12 · 1.5H2O4S
Y0001099
Valaciclovir impurity G, European Pharmacopoeia (EP) Reference Standard
C7H10N2
1707894
Valacyclovir Related Compound G, United States Pharmacopeia (USP) Reference Standard
C7H10N2