Organosilica colloids as nitric oxide carriers: Pharmacokinetics and biocompatibility.

Nitric oxide (NO) is a potential therapeutic agent for various diseases. However, it is challenging to deliver this unstable, free-radical gaseous molecule in the body. Various nanoparticle-based drug delivery systems have been investigated as promising NO carriers without detailed characterization of their biological fate. The purpose of this study is to investigate the pharmacokinetics and biocompatibility of organosilica-based NO-delivering nanocarriers. Two distinct NO nanoformulations, namely NO-SiNP-1 and NO-SiNP-2, were prepared from a thiol-functionalized organosilane using nanoprecipitation and direct aqueous synthesis, respectively. During the preparation, the thiol group was converted to S-nitrosothiol (SNO) under a nitrosation condition. The final products contain SNO-loaded organosilica particles of similar sizes (~130 nm), but of different morphologies and surface charges (between the two formulations). In the in vitro release kinetics study, NO-SiNP-1 exhibited a much slower NO release rate than NO-SiNP-2 (by 5-fold); therefore, the former is considered as a slow NO releaser, and the latter a fast NO releaser. However, in the rat pharmacokinetic study (IV bolus of 50 µmol/kg), NO-SiNP-1 was rapidly eliminated from the blood (within 20 min); in contrast, NO-SiNP-2 was slowly eliminated with an extended circulation time of 12 h for plasma SNO, along with markedly higher plasma levels of nitrite and nitrate. The two formulations are generally biocompatible. In conclusion, the paper presents contrast biological fates of two organosilica colloidal formulations for nitric oxide delivery.

Turning proteins into hydrophobic floatable materials with multiple potential applications.

HYPOTHESIS: Protein hydrogels are water-rich structure of cross-linked protein networks. The preparation of dry gels is conceptually simple. However, reports on innovative use of dry protein hydrogels are scarce, possibly because water removal would diminish intended properties. Here, an oil-like thiol-organosilane is proposed as a protein hydrogel-promoting agent that mediates the formation of hydrophobic composite gel networks with promising properties upon drying. EXPERIMENTS: 3-Mercaptopropyltrimethoxylsilane (MPTMS) was used to transform aqueous albumin solutions into hydrogels. The gelation conditions were systematically investigated and optimized by varying various parameters, including temperature, pH, and the concentrations of MPTMS, albumin, and phosphate. The hydrogels were freeze-dried to obtain dry gel monoliths. The morphology of gel structure was evaluated using FE-SEM. The following properties of the dry monoliths were further evaluated: water uptake, floatability, drug loading and release, water contact angles, bulk densities, and oil adsorption. Mechanistic investigation included FTIR and fluorescence quenching determinations, and the study of emulsion properties. FINDINGS: An unprecedented protein-organosilane composite hydrogel was synthesized in a one-step reaction, at neutral pH and ambient conditions. Freeze-dried gel monoliths exhibited excellent hydrophobicity and floatability (immediate floating and lasting for >7 days on water). The proposed material may find novel applications in floating drug delivery and environmental clean-up of oil spills.

Facile green synthesis of organosilica nanoparticles by a generic "salt route".

Colloidal silica has wide applications and the global demand of specialty silica is continually increasing. Therefore, it is significant to develop a synthetic method that is simple, versatile, energy-saving, ecologically benign, and easily scalable. Biomimetic synthesis of colloidal silica represents a promising strategy; however, it often requires the synthesis or extraction of specialized macromolecules. In this paper, we present a novel aqueous, one-pot, and green route for synthesis of organosilica nanoparticles. The reaction systems contain only water, an organosilane precursor, a salt, and a commonly used surfactant or amphiphilic polymer. The reaction was performed at ambient conditions without adding any additional solvent, energy, and harsh chemicals. The key findings include the novel identification of 5 salts (i.e. nitrite, fluoride, dibasic phosphate, acetate, and sulfite) that can catalyze organosilica condensation and the resulting formation of nano-colloids. Moreover, the presence of amphiphilic molecules is essential for salt catalysis at low salt concentrations and at nearly neutral pH. Solid-state NMR and in-situ ATR-FTIR studies confirmed that organosilica condensation is highly efficient under the mild reaction condition. In conclusion, the present study demonstrates that "soft" interaction between salts and surfactants (or polymers) can be utilized to construct an effective platform for synthesis of "hard" organosilica particles. The proposed method is generic and applicable to a wide range of commonly used surfactants (viz. non-ionic, anionic, cationic) and amphiphilic polymers, as well as to organosilanes with various hydrophobic functional groups (e.g. mercaptopropyl, vinyl, and methyl).

Silica Ouzo Effect: Amphiphilic Drugs Facilitate Nanoprecipitation of Polycondensed Mercaptosilanes.

Amphiphilic drugs are therapeutic agents whose molecular structures contain both hydrophobic and hydrophilic portions. Here we report a systematic study on how amphiphilic drugs can assist in silica nanoprecipitation. 3-Mercaptopropyltrimethoxysilane (MPTMS) was used as the sole silica material and 12 amphiphilic drugs spanning a wide spectrum of therapeutic categories were included. MPTMS polycondensation was conducted in a DMSO-based organic phase. After a sufficient time, particle formation was induced by injecting a small amount of the organic phase into a water solution containing various amphiphiles. The results show that all amphiphilic drugs studied exerted concentration-dependent facilitating effect on nanoparticle formation. Under certain preparation conditions, the particle solution showed physical stability over a long period and the formed particles could be as small as 100 nm. By systematically varying drug concentrations and injection volumes, the ability of each amphiphile to promote nanoprecipitation can be quantified and compared, based on two novel indices: the area under the critical volume-concentration curve (AUC) and the critical stabilization concentration (CSC). We demonstrate that both ability indices significantly correlated with the drug's log P and critical micelle concentrations (CMC). Furthermore, we have optimized the aging and particle purification condition and extensively characterized our system through comprehensive TEM and zeta-potential measurements, as well as determinations for drug entrapment and release. In conclusion, we have established a quantitative structure-activity relationship for amphiphilic small-molecular drugs in their ability to interact with poly(mercaptopropyl)silsesquioxane species and form nanoparticles via solvent shifting. We speculate that both hydrophobic and electrostatic interactions play important roles in the formation and stabilization of nanoparticles.

An efficient S-NO-polysilsesquioxane nano-platform for the co-delivery of nitric oxide and an anticancer drug.

Codelivery of nitric oxide (NO) and drugs based on a single nanocarrier is a promising therapeutic strategy. Here, we report a one-step nanoprecipitation method to generate nanoparticles that possess simultaneous NO-donating and doxorubicin releasing properties. S-Nitroso polysilsesquioxane acts like an avid "drug sponge" that attracts drug molecules into nanospheres.

LbL Assembly of Albumin on Nitric Oxide-Releasing Silica Nanoparticles Using Suramin, a Polyanion Drug, as an Interlayer Linker.

Preformed protein corona of nanoparticles can be utilized as a promising formulation strategy for improving nano drug delivery. Nitric oxide (NO) is a labile molecule with extensive therapeutic implications. In this study, we test whether preformation of protein coatings can enhance the performance of NO-delivering nanoparticles. S-Nitroso (SNO) silica nanoparticles (SNO-SiNPs) were prepared using a nanoprecipitation method. For the first time, bovine serum albumin (BSA) was used to coat NO-releasing nanoparticles, facilitated by a polyanionic drug, suramin, under a layer-by-layer (LbL) scheme. Bare and coated nanoparticles were characterized by zeta-potential, size, and spectroscopic measurements. We demonstrate that albumin/suramin-surface coassembly has advantages in preventing particle aggregation during lyophilization, controlling NO release and exerting an enhanced anticancer effect.

Versatile synthesis of thiol- and amine-bifunctionalized silica nanoparticles based on the ouzo effect.

In this article, we report a novel, nanoprecipitation-based method for preparing silica nanoparticles with thiol and amine cofunctionalization. (3-Mercaptopropyl)trimethoxysilane (MPTMS) and 3-aminopropyltrimethoxysilane (APTMS) were used as the organosilane precursors, which were subjected to acid-catalyzed polycondensation in an organic phase containing a water-miscible solvent (e.g., dimethyl sulfoxide). A pale colloidal solution could be immediately formed when the preincubated organic phase was directly injected into water. The initial composition ratio between MPTMS and APTMS is an important factor governing the formation of nanoparticles. Specifically, large, unstable micrometer-sized particles were formed for preparation using MPTMS as the sole silane source. In contrast, when APTMS was used alone, no particles could be formed. By reducing the fraction of APTMS (or increasing that of MPTMS) in the initial mixture of organosilanes, the formation of nanometer-sized particles occurred at a critical fraction of APTMS (i.e., 25%). Remarkably, a tiny fraction (e.g., 1%) of APTMS was sufficient to produce stable nanoparticles with a hydrodynamic diameter of about 200 nm. Other factors that would also affect particle formation were determined. Moreover, an interesting temperature effect on particle formation was observed. The TEM micrographs show spherical nanospheres with mean sizes of 130-150 nm in diameter. The solid-state (29)Si NMR spectra demonstrate that the hybrid silica materials contain fully and partially condensed silicon structures. The bifunctionalized silica nanoparticles have positive zeta potentials whose magnitudes are positively correlated with the amount of APTMS. The total thiol content, however, is negatively correlated with the amount of APTMS. The cationic nanoparticles can bind an antisense oligonucleotide in a composition-dependent manner.

Direct formation of S-nitroso silica nanoparticles from a single silica source.

Nitric oxide (NO) is a ubiquitous molecule in the body. Because of its multiple pathophysiologic roles, the potential for treating various diseases by the exogenous administration of NO has been under intensive investigation. However, the unstable, radical nature of NO poses a major challenge to the effective delivery of NO. Previously, silica nanoparticles synthesized by the traditional method have been developed into NO-carrying systems. In the present study, for the first time NO-carrying silica nanoparticles were prepared from a single silica precursor using a simple nanoprecipitation method. (3-Mercaptopropyl)-trimethoxysilane (MPTMS) was used as the sole silane source, which was subjected to acid-catalyzed S-nitrosation and condensation reactions in a one-pot organic phase. S-Nitroso silica nanoparticles (SNO-SiNPs) were then produced by injecting a smaller quantity of the organic phase into a larger amount of water without surfactants. Various preparation parameters were tested to obtain optimized conditions. Moreover, a phase diagram demonstrating the ouzo effect was constructed. The prepared SNO-SiNPs were spherical particles with a tunable size in the range of 100-400 nm. The nanoparticles in aqueous dispersions exhibited high colloid stability, possibly resulting from highly negatively charged surfaces. The result of solid-state (29)Si NMR shows the predominance of T(2) and T(3) silicon structures, suggesting that nanoparticles were formed from polycondensed silica species. In conclusion, NO-loaded silica nanoparticles have been directly prepared from a single silane precursor using a surfactant-free, low-energy, one-step nanoprecipitation approach. The method precludes the need for the initial formation of bare particles and subsequent functionalization steps.