pH- and temperature-responsive hydrogels for delivery of angiogenic growth factors

Therapeutic angiogenesis, or the delivery of angiogenic growth factors to promote revascularization, is a promising approach to treat ischemic heart disease. However, improved drug delivery systems (DDSs) are needed to provide effective therapy. Stimuli-responsive hydrogels can be designed take advantage of the low pH environment of ischemic myocardium (pH 6--7). In particular, polymers that are soluble at pH 7.4 and 37°C but form physical gels under conditions of intermediate acidity (pH 6--7) and 37°C could facilitate spatio-temporal control of angiogenic growth factor delivery and improve the efficacy of therapeutic angiogenesis methods.;The pH- and temperature-responsive random copolymer, poly(N-isopropylacrylamide-co-propylacrylic acid) (p[NIPAAm-co-PAA]), was synthesized by reversible addition fragmentation chain transfer polymerization. Viscoelastic properties of this material as functions of pH, temperature, and composition were quantified by rheometry. At physiologic pH (7.4) and 5 w/v %, the polymer did not form gels, but rather remained soluble at temperatures as high as 50°C. At lower pH values (pH<5.5) the polymer was a liquid at 20°C but exhibited a sol-gel phase transformation with increasing temperature and existed as a gel at 37°C. Incorporation of the hydrophobic monomer, butyl acrylate (BA), into the random copolymer raised the pH of gel formation to greater than 6.0 at 37°C. Drug loading studies demonstrated that p(NIPAAm-co-PAA) hydrogels are able to provide sustained, pH-dependent release of vascular endothelial growth factor over a period of at least three weeks. P(NIPAAm-co-PAA-co-BA) was used to deliver basic fibroblast growth factor (bFGF) via injection into infarcted rat myocardium. Following 4 weeks of treatment in vivo, there was a 33% increase in capillary density in rats treated with polymer+bFGF compared to untreated saline control rats (p<0.001). Treatment with polymer+bFGF for 4 weeks resulted in a 2-fold improvement in relative blood flow to the infarct region compared to day 0 (p<0.05). By responding to local changes in pH and temperature in an animal model of ischemia, this DDS was able to provide sustained, local delivery of bFGF and achieve a therapeutic response. Also, this hydrogel could be used for drug delivery to other regions of local acidosis as found in wound healing or tumors.