We have previously described the photoactivated depot (PAD) approach for the minimally invasive, continuously variable delivery of insulin. In the PAD approach, an inert insulin depot is injected under the skin. An LED placed on the skin then triggers release of native insulin from the depot via transdermal irradiation. The dose and timing can be controlled by varying the intensity and duration of irradiation. This minimally invasive system has potential advantages over existing delivery methods such as pumps. The most important of these advantages is the elimination of the physical connection of the outside and inside of the patient, which is typically achieved through a cannula. This cannula is easily snagged, crimped and bio-fouled. We have demonstrated the efficacy of the PAD approach in vivo with a first-generation material in which insulin is linked to an insoluble polymer via a photocleavable (PC) group. However, this polymer was bulky, leading to issues with total insulin loading, injectability and biodegradability. Thus, we sought to make new PAD materials by replacing the polymer with small tags that are able to confer the same properties that the polymer did, namely insolubility, but in a more efficient way.<br/>In this work, two approaches are discussed to make tag-based PAD materials. Firstly, non-polar synthetic and peptidic molecules were linked to the insulin via a PC group. This approach resulted in materials with very low solubility at physiological pH until photolysis (or light irradiation) released fully soluble, native insulin. In our second approach, we synthesized positively charged tags and linked these to insulin via the PC group thereby raising the isoelectric point (pI) of insulin from 5.4 to 7.2. These materials were soluble at a formulation pH of 4, but precipitated at pH 7.2 which is the approximate pH of the skin. With these two approaches, we were able to make new materials with a 20-fold improvement in insulin density compared to first generation PAD materials. A further potential advantage of using tags to toggle insulin solubility is their ease of post-photolysis clearance from the depot site. In addition, these PAD materials can be milled into fine micron-sized particles. Highly concentrated suspensions of these particles are injectable through a 31G needle and have the potential to provide multiple days worth of controlled insulin release from a single injection.

Insulin photoactivated depots incorporating small tags for highly efficient light triggered solubility modulation

2019 Fall National Meeting

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