Visually controlled pulsatile release of insulin from chitosan poly-acrylic acid nanobubbles triggered by focused ultrasound

Insulin therapy is the most effective way to control the blood glucose value of diabetic patients. The most effective administration route for insulin is subcutaneous injection because bioavailability for non-injection administration is low and unstable. However, patients often need a multiple daily insulin injection regimen to control basal and postprandial blood glucose, which causes various complications. Controlled pulsatile drug release technology using ultrasound as an external stimulus source is a very promising method to avoid multiple injections of insulin. However, most of the drug-loaded microbubbles used for ultrasound-mediated treatment have a short half-life, which limits their use in controlled pulsatile drug release. More importantly, how to control insulin release is still a challenge. In this paper, chitosan poly-acrylic acid nanobubbles as drug carriers of insulin were prepared to achieve a visually controlled pulsatile release of insulin triggered by focused ultrasound. The experimental results in vivo demonstrated that nanobubbles were stable enough to achieve long-term visualization for 7 days after intramuscular injection in rats. Under the guidance of ultrasound imaging, it is visible to find the position and observe the gray values change of nanobubbles. Thus, when triggered by focused ultrasound, the amount of insulin could be accurately pulsatile released from nanobubbles. In vivo experiments in rats showed that the visually controlled pulsatile release of insulin could be achieved for a long time, up to 3 consecutive days. The blood glucose level could be repeatedly reduced by focused ultrasound irradiation with just one injection. Our research provided a promising way for visually controlled pulsatile release of insulin, which would significantly reduce the injection frequency of insulin.