Bioresorbable pH- and temperature-responsive injectable hydrogels-incorporating electrosprayed particles for the sustained release of insulin

Abstract

In situ-forming injectable hydrogels are attractive delivery vehicles not only for the controlled delivery of drugs and proteins but also for the controlled the delivery of nanometer sized particles. In this study, pH- and temperature-responsive pentablock copolymers were synthesized by the conjugation reaction between carboxylic groups of oligo (serine) and alcohol groups of temperature-responsive triblock copolymers, poly (ε-caprolactone)-b-poly (ethylene glycol)-b-poly (ε-caprolactone). Owing to their pH- and temperature-responsive property, the pentablock copolymers were found to be soluble at high pH, and transformed to viscoelastic gel at the physiological condition (pH 7.4, 37 °C). Furthermore, the free-flowing pentablock copolymer sols form a stable hydrogel depot on the back of Sprague-Dawley rats. The hydrogel depot was found to be degradable in a controlled manner and bioresorbable after one month. Insulin-incorporated nanosized chitosan particles were prepared via the electrospraying method and mixed with the pentablock copolymer solution to control the release of insulin. At high pH, the negatively charged pentablock copolymers and insulin-incorporated chitosan particles form an ionic complex through electrostatic interaction. Interestingly, in physiological conditions, the complex formed a viscoelastic gel and controlled the release of insulin in a spatiotemporal-controlled manner for over one month with remarkable inhibition of first-burst of insulin. These results demonstrated that modular design of injectable smart hydrogels with chitosan particles showing great prospect to control the delivery of insulin.