Mesoporous Silica Nanoparticle-Based Double Drug Delivery System for Glucose-Responsive Controlled Release of Insulin and Cyclic AMP

• Published in: Journal of the American Chemical Society 2009-06, Vol.131 (24), p.8398-8400
• Main Authors: Zhao, Yannan, Trewyn, Brian G, Slowing, Igor I, Lin, Victor S.-Y
• Format: Article
• Language: English
• Subjects: Animals; Boronic Acids - administration & dosage; Boronic Acids - chemistry; Cyclic AMP - administration & dosage; Cyclic AMP - chemistry; Delayed-Action Preparations - administration & dosage; Delayed-Action Preparations - chemical synthesis; Delayed-Action Preparations - chemistry; Delayed-Action Preparations - pharmacology; Drug Delivery Systems - methods; Fibroblasts - drug effects; Fibroblasts - metabolism; Gluconates - chemistry; Glucose - chemistry; Glucose - metabolism; HeLa Cells; Humans; Insulin - administration & dosage; Insulin - analogs & derivatives; Insulin - chemistry; Mice; Nanoparticles - administration & dosage; Nanoparticles - chemistry; Rats; Silicon Dioxide - administration & dosage; Silicon Dioxide - chemistry; Silicon Dioxide - pharmacology
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/ja901831u

A boronic acid-functionalized mesoporous silica nanoparticle-based drug delivery system (BA-MSN) for glucose-responsive controlled release of both insulin and cyclic adenosine monophosphate (cAMP) was synthesized. Fluorescein isothiocyanate-labeled, gluconic acid-modified insulin (FITC-G-Ins) proteins were immobilized on the exterior surface of BA-MSN and also served as caps to encapsulate cAMP molecules inside the mesopores of BA-MSN. The release of both G-Ins and cAMP was triggered by the introduction of saccharides. The selectivity of FITC-G-Ins release toward a series of carbohydrate triggers was determined to be fructose > glucose > other saccharides. The unique feature of this double-release system is that the decrease of FITC-G-Ins release with cycles can be balanced by the release of cAMP from mesopores of MSN, which is regulated by the gatekeeper effect of FITC-G-Ins. In vitro controlled release of cAMP was studied at two pH conditions (pH 7.4 and 8.5). Furthermore, the cytotoxicity of cAMP-loaded G-Ins-MSN with four different cell lines was investigated by cell viability and proliferation studies. The cellular uptake properties of cAMP-loaded FITC-BA-MSN with and without G-Ins capping were investigated by flow cytometry and fluorescence confocal microscopy. We envision that this glucose-responsive MSN-based double-release system could lead to a new generation of self-regulated insulin-releasing devices.