(323e) Nanoparticle Delivery of Stabilized Angiogenic Growth Factors

Defects in blood vessel growth and proliferation have been strongly implicated in myocardial ischemia leading to heart disease. Alleviating this condition traditionally requires stenting or grafting of a transplanted vessel. Therapies promoting localized myocardial angiogenesis may circumvent the need for these invasive and often temporary treatments. Despite the complexity of angiogenic signaling pathways, vascular endothelial growth factor isoform 165 (VEGF165) and fibroblast growth factor-2 (FGF2) have emerged as powerful angiogenic cytokines. Clinical trials exploring intravenous (IV) administration of these growth factors for angiogenesis, however, have thus far proved unsuccessful. Growth factors such as VEGF typically suffer from a short in vivo half-life, multiple complex activities, and rapid degradation. What is needed, therefore, is a method to stabilize, target and sustain the concentration of growth factors to promote myocardial angiogenesis via facile IV administration as an alternative to invasive and expensive surgical procedures. Here we take advantage of VEGF and FGF2 binding to polyanions, which results in an increase in thermal stability. Excess polyanions charges can then be utilized to form polyelectrolyte complexes when mixed with an appropriate polycation. We have investigated the effect of molecular mass and mixing ratios of polyelectrolytes on polymer complex properties. Varying polymer molar mass and mass ratio of polyelectrolytes (e.g. dextran sulfate (polyanion) and chitosan (polycation)) resulted in direct control over polymer complex diameter and zeta potential including the production of small, ~200 nm, complexes.