Controlled delivery of VEGF via modulation of alginate microparticle ionic crosslinking

Clinical application of therapeutic angiogenesis is hampered by a lack of viable systems that demonstrate controlled, sustained release of vascular endothelial growth factor (VEGF). Alginate has emerged as a popular material for VEGF delivery; however most alginate-based systems offer limited means to control the rate of VEGF release beyond reducing the VEGF:alginate ratio to suboptimal efficiency. This study describes methods to control the release of VEGF from small (<10 microm mean diameter) alginate microparticles via the use of different ionic crosslinkers. Crosslinking with Zn(2+) versus Ca(2+) reduced VEGF diffusional release and the combination of discrete populations of either Zn(2+)- or Ca(2+)-crosslinked particles allowed for control over the sustained release profiles for VEGF. The particle preparations were non-toxic and VEGF was bioactive after release. These results demonstrate that ionic modulation of alginate crosslinking is a viable strategy for controlling release of VEGF while retaining the high protein:polymer ratio that makes alginate an attractive carrier for delivery of protein therapeutics.