DEVELOPMENT OF AN INJECTABLE PH- AND TEMPERATURE-RESPONSIVE HYDROGEL DRUG DELIVERY SYSTEM.

Abstract

Regions of local acidosis, such as that seen in myocardial ischemia, offer a target for stimuli-sensitive drug delivery systems. Hydrogels are polymer networks that are capable of entrapping significant amounts of water and can be designed to respond to stimuli such as temperature, pH, light, and electric fields. These properties make them highly attractive for drug delivery systems because of their biocompatibility and potential for drug targeting. In particular, reversible hydrogels are attractive because they can be designed to be soluble under normal physiologic conditions but form a gel under other conditions, such as decreased pH. In this study, we investigated the sol-gel properties of a pH- and temperature-sensitive polymer and assessed the ability of this polymer to be developed into an injectable hydrogel drug delivery system for ischemic cardiac tissue. Poly(N-isopropylacrylamide-co-propyl acrylic acid) (p(NIPAAm-co-PAA)) was synthesized by reversible addition fragmentation chain transfer (RAFT) polymerization. The feed composition of the pH-sensitive component, PAA, was varied between 0 and 20 mol%. Polymer was characterized by gel permeation chromatography and proton nuclear magnetic resonance to determine the molecular weight and polymer composition, respectively. Polymer samples were dissolved in phosphate buffer, and then pH was adjusted between 4.5 and 7.0. One-milliliter samples were loaded onto a rheometer to quantify viscoelastic properties. P(NIPAAm-co-PAA) polymers of varying PAA content were successfully synthesized by RAFT. At physiologic pH (7.4), the polymer did not form a gel but rather remained in the soluble state at all temperatures. However, at low pH (below approximately pH 5.5), with increasing temperature (in a physiologically relevant range), the polymers underwent a phase change from a clear liquid, to a cloudy liquid, and finally to a gel. As the pH was decreased further, the gelation temperature for a given polymer composition also decreased. In conclusion, by varying the relative ratio of NIPAAm and PAA in p(NIPAAm-co-PAA), the temperature and pH at which a gel forms can be controlled. Future studies will investigate the drug-release properties of this system.