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.

The interactions of mesoporous silica nanoparticles (MSNs) of different particle sizes and surface properties with human red blood cell (RBC) membranes were investigated by membrane filtration, flow cytometry, and various microscopic techniques. Small MCM-41-type MSNs (∼100 nm) were found to adsorb to the surface of RBCs without disturbing the membrane or morphology. In contrast, adsorption of large SBA-15-type MSNs (∼600 nm) to RBCs induced a strong local membrane deformation leading to spiculation of RBCs, internalization of the particles, and eventual hemolysis. In addition, the relationship between the degree of MSN surface functionalization and the degree of its interaction with RBC, as well as the effect of RBC−MSN interaction on cellular deformability, were investigated. The results presented here provide a better understanding of the mechanisms of RBC−MSN interaction and the hemolytic activity of MSNs and will assist in the rational design of hemocompatible MSNs for intravenous drug delivery and in vivo imaging. R ecent advancements in particle size and morphology control of mesoporous materials have led to the creation of nano-and submicrometer-sized mesoporous silica nanoparticles (MSNs). [1][2][3][4][5] The MSN materials with well-ordered cylindrical pore structures, such as MCM-41 and SBA-15, have attracted special interest in the biomedical field. 1 The large surface areas and pore volumes of these materials allow the efficient adsorption of a wide range of molecules, including small drugs, 6-10 therapeutic proteins, 11-13 antibiotics, 14,15 and antibodies. 16 Therefore, these materials have been proposed for use as potential vehicles for biomedical imaging, real-time diagnosis, and controlled delivery of multiple therapeutic agents. [6][7][8]10,[17][18][19][20][21][22][23][24][25] Despite the considerable interest in the biomedical applications of MSNs, relatively few studies have been published on the biocompatibility of the two most common types of MSNs (MCM-41 and SBA-15). [26][27][28][29] Asefa and co-workers reported that the cellular bioenergetics (cellular respiration and ATP levels) were inhibited remarkably by large SBA-15 nanoparticles, but the inhibition was greatly reduced by smaller MCM-41-type nanoparticles. 26 These differences in the disruption of cellular bioenergetics are believed to be caused by the different surface areas, number of surface silanol groups, and/or particle sizes of both types of material. A recent study by Kohane and collaborators on the systemic effects of MCM-41 (particle size ∼150 nm) and SBA-15 (particle size ∼800 nm) MSNs in live animals revealed interesting findings regarding their biocompatibility. 27 While large doses of mesoporous silicas administered subcutaneously to mice appear to be relatively harmless, the same doses given intravenously or intraperitoneally were lethal. 27 A possible reason for the severe systemic toxicity of MSNs when injected intravenously could be the interactions of the nanoparticles with blood cells.Our initial studies...

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