Light Triggered Isoelectric Point and Solubility Shifts Applied to Photoactivated Insulin Depots

Abstract

We previously described photoactivated insulin depot, a minimally invasive technique of insulin delivery (1). In this approach, an inert photoactivated depot is injected under the skin. Exposure of the depot to light triggers the release of native insulin into the blood. First‐generation materials were designed to have insulin chemically attached to an insoluble polymer (for insolubility) via photocleavable linker. Though this material is effective in studying the approach in vitro and in vivo (2), it has multiple problems associated with the insoluble polymer. About 95% of the depot consisted of the non‐therapeutic polymer, which is non‐biodegradable and difficult to inject into an animal.In this work, we solved these problems by eliminating the polymer and reacting insulin with a photocleavable group containing positively charged groups. The result is an insulin with an altered pI and thus, with a different solubility (3). We achieved the insulin's insolubility by shifting its pI to physiological pH. We observed an increase 0.65 units of pI of insulin with the addition of a single positive charge. We raised the pI of insulin from 5.4 to 7.2, specifically by the addition of two positively charged groups and quenching one negative charge (carboxylate) on insulin. This material has high solubility in acidic pH, and hence can be a soluble formulation. But upon injection at skin pH, it is observed to precipitate as a depot. Upon exposure to light, the positively charged groups are removed to generate the native insulin, which can then be absorbed into the blood due to its high solubility. These materials have high insulin density (91% w/w), are soluble in acidic formulations and upon photolysis, will result in charged, soluble and excretable by‐products without leaving any traces of depot at the site of injection.Support or Funding InformationNIH‐1DP3DK106921‐01, University of Missouri Fast Track Award and UMKC School of Pharmacy Dean's Bridge FundThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.