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

Abstract

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.

Enhanced oral bioavailability of insulin-loaded solid lipid nanoparticles: pharmacokinetic bioavailability of insulin-loaded solid lipid nanoparticles in diabetic rats

“…Several drug carriers have been proposed to increase the oral bioavailability of insulin including microemulsions (Cho & Flynn 1989), liposomes (Spangler, 1990), microspheres (Morishita et al, 1993;Timmy, 2002) and polymeric nanoparticles (Lin et al, 2007;Zhang et al, 2009;Zhao et al, 2009;Fonte et al, 2015). However, such carrier systems have disadvantages like low stability, low drug carrying capacity, leakage of entrapped drug and toxicity of the residual solvents and surfactants used (Gowthamarajan & Kulkarni, 2003).…”

Enzyme-Responsive Intracellular Controlled Release Using Nanometric Silica Mesoporous Supports Capped with “Saccharides”

“…Lin et al developed capped materials using mesoporous scaffoldings capped with CdS, gold or magnetic nanoparticles attached to the SMPS through disulfide linkages that were broken up upon addition of certain reducing compounds. [44][45][46][47][48][49][50][51][52][53][54] Also, the rupture of disulfide linkages in molecular based systems 55 and polymeric networks have been used for on-command delivery. 56,57 Zink and Stoddart prepared several gated materials triggered by redox inputs that were equipped with nanovalves based on rotaxanes and pseudorotaxanes containing redox active moieties.…”

Protein-gold clusters-capped mesoporous silica nanoparticles for high drug loading, autonomous gemcitabine/doxorubicin co-delivery, and in-vivo tumor imaging

“…[55] Insulin molecules were grafted on the MSN surface capped with a glucose-responsive system, while the pores were loaded with the second cargo. Palanikumar and coworkers very recently demonstrated than the loading capacity of MSN could reach 80 wt% through higher drug concentrations in loading solutions, [56,57] unlike the typical 10 wt% threshold of previous reports.…”