Visible-Light-Activated High-Density Materials for Controlled in Vivo Insulin Release
| Autor: | Simon H. Friedman, Bhagyesh R. Sarode, Karen Kover |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
Azides
Light Polymers medicine.medical_treatment Pharmaceutical Science Trimer 02 engineering and technology Photochemistry 030226 pharmacology & pharmacy Article 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Coumarins In vivo Drug Discovery medicine Insulin Photolysis Photodissociation 021001 nanoscience & nanotechnology Solubility chemistry Click chemistry Molecular Medicine Amine gas treating Azide 0210 nano-technology Visible spectrum |
| Zdroj: | Molecular Pharmaceutics. 16:4677-4687 |
| ISSN: | 1543-8392 1543-8384 |
| Popis: | In this work we describe the synthesis, characterization and ultimate in-vivo assessment of second generation insulin photoactivated depot (PAD) materials. These are the first to use visible light to stimulate insulin release, and have in-vivo performance that is twenty eight fold improved relative to first generation materials. This improvement is due to two major factors linked to the utilized chemistry: 1) We have incorporated the coumarin photocleavable group, which increases the photo-release wavelength into the visible range, enhancing tissue penetration of the light and 2) Photo-toggling of insulin solubility is produced by linking three insulin molecules to a central bridge via light cleaved groups, and not by bonding to a large polymer. The resulting trimer is therefore highly dense (87% insulin dry w/w) but retains the insolubility required of the approach. Only after irradiation with visible light is native, soluble insulin released from the dermal depot. This high density increases the amount and ease of insulin release, as the density of photolytic groups is 10–20 fold higher than in polymer based first generation materials. We have synthesized new azide- terminated coumarin linkers that we react with the amine groups of insulin. Using mass spectrometry methods we identify the sites of reaction and purify individual isomers, which we demonstrate have in-vitro photolysis rates that are within a factor of two of each other. We then reacted these terminal azide groups with a tri-dentate strained alkyne linker. We show that the resulting insulin trimer is highly insoluble, but can be milled into injectable particles that release insulin only in response to light from a 406nm light source. Finally, we demonstrate that these materials have significantly improved in-vivo performance, releasing twenty eight fold more insulin on a per energy basis than first generation materials. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|