In vivo variable and multi-day response from an insulin-releasing photoactivated depot

Nadendla, Karthik; Chintala, Swetha; Kover, Karen; Friedman, Simon H.

doi:10.1016/j.bmcl.2023.129388

Cited by 1 publication

(7 citation statements)

References 23 publications

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“…This supports the idea that the signal is due to released insulin and not the precursor material itself (which is not detected by ELISA). We have recently observed a similar leaching phenomenon with a related PAD material, so-called CD-insulin, which also uses the nonpolar tag approach . This is an area of active inquiry for us as understanding and manipulating this slow basal release can be a very useful addition to the PAD approach.…”

Section: Resultsmentioning

confidence: 77%

“…Combined, this suggested that PAD materials based on the thio-coumarin PC group could potentially be effective in the subcutaneous layer where DMNPE-based materials failed (Figure ). To make the new thio-coumarin based material, we utilized our nonpolar tag approach, in which a highly nonpolar group is attached to the target protein (insulin in this case) via the PC group. , If correctly selected, the nonpolar group confers insolubility upon the adduct, allowing the material to remain at the site of injection until irradiation releases insulin. To synthesize this material, we started with a commercially available amino coumarin (Figure ) and alkylated it twice to introduce two strongly nonpolar 10 carbon chains.…”

Section: Resultsmentioning

confidence: 99%

“…We then assessed the material for in vivo efficacy in the subcutaneous space in a streptozotocin-induced diabetic rat model. The in vivo studies were performed as previously described. ,, Immediately before an animal study, we milled the isomer-3 thio-coumarin insulin in PBS buffer using a hand-held homogenizer for 1 min as previously described . This produces small particles that, while insoluble, are still injectable through the lumen of a 27G syringe needle.…”

Section: Resultsmentioning

confidence: 99%

“…For these reasons, the subcutaneous layer is the standard injection site for insulin and other peptides. Unfortunately, when used in the subcutaneous space, our previously described light-activated materials fail, showing no insulin release upon irradiation . Specifically, in previous work, we showed that a PAD material (CD-insulin, or cyclo-dodecyl insulin) based on the 365 nm DMNPE (dimethoxy nitro phenyl ethyl) group showed insulin release when injected in the dermal layer but none when injected in the subcutaneous layer.…”

Section: Introductionmentioning

confidence: 95%

“…This is particularly true of peptide hormone drugs such as insulin, whose requirements continuously vary depending on multiple factors, including diet and activity. The only clinically used method of variable delivery for these therapeutics is through a pump and a cannula or microneedle. − However, pumps and cannulas are beset by a wide range of problems including crimping, snagging, infection, biofouling, and occlusion. − Previously, we have demonstrated that we can instead control the release of insulin from light-stimulated materials injected into the dermal layer of the skin. − These release bioactive insulin and produce robust reductions of blood glucose without the need for a pump. We call this the photoactivated depot or PAD approach.…”

Section: Introductionmentioning

confidence: 99%

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A Green Light-Activated Insulin Depot with Ultrafast In Vivo Efficiency in the Subcutaneous Space

Ansong,

Kover,

Shah

et al. 2024

ACS Biomater. Sci. Eng.

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In this work, for the first time, we demonstrate light control of a therapeutic protein's release from a depot in the subcutaneous layer of the skin. The subcutaneous layer is a standard location for therapeutic protein depots due to its large size and ease of access, but prior attempts to utilize this space failed because insufficient light can reach this deeper layer. An analysis of existing biophysical literature suggested that an increase of photoactivation wavelength from 365 to 500 nm could allow an increase of depot irradiation in the subcutaneous by >100-fold. We therefore used a green light-activated thiocoumarin-based material and demonstrated robust release of a therapeutic, insulin, in response to skin illumination with an LED light source. We further demonstrated that this release is ultrafast, as fast or faster than any commercially used insulin, while maintaining the native insulin sequence. This release of insulin was then accompanied by a robust reduction in blood glucose, demonstrating the retention of bioactivity despite the synthetic processing required to generate the material. In addition, we observed that the material exhibits slow basal release of insulin, even in the absence of light, potentially through biochemical or photochemical unmasking of insulin. Thus, these materials can act much like the healthy pancreas does: releasing insulin at a slow basal rate and then, upon skin irradiation, releasing an ultrafast bolus of native insulin to reduce postprandial blood glucose excursions.

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Section: Resultsmentioning

confidence: 77%

Section: Resultsmentioning

confidence: 99%