Injectable Microparticle-Nanoliposome Hydrogel for Extended Release of Small Hydrophilic Molecules

Achieving sustained local release of small hydrophilic drugs is challenging and is particularly important when the drugs are toxic. To address these challenges, we developed a hybrid system comprising drug-containing microparticles embedded within a nanoliposomal hydrogel matrix. This system forms through salt-induced gelation using physiologically relevant sodium chloride concentrations (0.9%), allowing for microparticle encapsulation without harsh chemical processes. In vitro, the hybrid system exhibited a slower release of encapsulated cargo compared to microparticles or hydrogel alone. In vivo proof of principle was provided with tetrodotoxin (TTX), a small hydrophilic and ultrapotent local anesthetic, which can cause systemic toxicity if the release is not controlled. Encapsulating TTX within the microparticles of the hybrid system provided a very prolonged nerve block (∼100 h), without systemic toxicity. These findings demonstrate that the hybrid system of microparticles within a nanoliposome gel enabled sustained release, improved local drug retention, and provided a safer and prolonged delivery of potent small-molecule therapeutics.