Nitric Oxide-Releasing Fumed Silica Particles:  Synthesis, Characterization, and Biomedical Application

Abstract

The preparation, characterization, and preliminary biomedical application of various nitric oxide (NO)-releasing fumed silica particles (0.2-0.3 microm) are reported. The tiny NO-releasing particles are synthesized by first tethering alkylamines onto the surface of the silica using amine-containing silylation reagents. These amine groups are then converted to corresponding N-diazeniumdiolate groups via reaction with NO(g) at high pressure in the presence of methoxide bases (e.g., NaOMe). N-Diazeniumdiolate groups were found to form more readily with secondary amino nitrogens than primary amino nitrogens tethered to the silica. Different alkali metal cations of the methoxide bases, however, have little effect on the degree of N-diazeniumdiolate formation. The N-diazeniumdiolate moieties attached on the silica surface undergo a primarily proton-driven dissociation to NO under physiological conditions, with an "apparent" reaction order somewhat greater than 1 owing to local increases in pH at the surface of the particles as free amine groups are generated. The rates of N-diazeniumdiolate dissociation are further related to the parent amine structures and the pH of the soaking buffer. The N-diazeniumdiolate groups also undergo slow thermal dissociation to NO, with zero-order dissociation observed at both -15 and 23 degrees C. It is further shown that the resulting NO-releasing fumed silica particles can be embedded into polymer films to create coatings that are thromboresistant, via the release of NO at fluxes that mimic healthy endothelial cells (EC). For example a polyurethane coating containing 20 wt % of NO-releasing particles prepared with pendant hexane diamine structure (i.e., Sil-2N[6]-N(2)O(2)Na) is shown to exhibit improved surface thromboresistivity (compared to controls) when used to coat the inner walls of extracorporeal circuits (ECC) employed in a rabbit model for extracorporeal blood circulation.

Inorganic/Organic Hybrid Silica Nanoparticles as a Nitric Oxide Delivery Scaffold

“…Zhang et al reported that the addition of a strong base such as sodium methoxide (NaOMe) during NO exposure promotes the deprotonation of the secondary amine nitrogen, thereby shifting the reaction equilibrium toward N-diazeniumdiolate formation. 24 Furthermore, the sodium ion serves as a countercation to stabilize the anionic N-diazeniumdiolate structure of 3 (see Supporting Information). When NaOMe was employed in this work, the conversion efficiencies increased more than 10-fold with typical yields of 54 -100% (see below for details).…”

“…On the basis of monitoring the amount of NO release, the concentration of N-diazeniumdiolate species (C diaz ) at any given time may be determined. 24 The dissociation kinetics of two representative N-diazeniumdiolates derived from AEAP3 and DET3 are shown in Figure 3. Plots of the natural logarithm of the N-diazeniumdiolate concentration (ln C diaz ) versus time yielded a linear relationship, with R 2 values typically ≥0.995 for all N-diazeniumdiolates examined (indicating first-order kinetic behaviors in all cases).…”

“…24 The silica particles prepared via this method released 0.56 μmol NO·mg −1 . 24 More recently, our laboratory reported an alternative strategy for preparing NO-releasing silica particles of variable sizes (d = 20 -500 nm), NO payloads (0.05 -1.78 μmol·mg −1 ), and NO release half-lives (0.1 -12 h). 25 Briefly, the NO-releasing silica nanoparticles were synthesized via the co-hydrolysis and condensation of aminoalkoxysilanes (NO donor precursors) and tetraalkoxysilanes (i.e., tetramethoxy-or tetraethoxysilane) followed by exposure to NO (5 atm, 3 d) in the presence of sodium methoxide (NaOMe) base to form N-diazeniumdiolates ( Figure 1A).…”

“…[26][27][28][29][30][31] Several NO donor micro-and nanoscale materials have been developed using a range of host macromolecules including albumin conjugates, 16 polylactic-co-glycolic acid copolymers, 17 polyethyleneimine microspheres, 18 polymethacrylate particles, 19,20 gold clusters, 21,22 dendrimers, 23 and silica particles. 24,25 Of these, silica scaffolds provide an attractive platform as NO delivery vehicles because of their physical and chemical versatility. [32][33][34][35] The ability to form tunable porous structures of various sizes with tailored surface functionalities has led to the use of silica nanoparticles in bioseparation and drug delivery systems.…”

Modulated nitric oxide delivery in three-dimensional biomaterials for vascular functionality

“…The first NO-releasing particles with covalent modification was reported by Zhang et al [83] Non-toxic amorphous fumed silica particles (200-300 nm in diameter) were tethered with aminecontaining silylation reagents followed by diazeniumdiolation. The diazeniumdiolated fumed silica particles released NO under physiological conditions via primarily the proton-driven dissociation associated with negligible thermal dissociation.…”