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Nanoparticles, Silicon dioxide, Polymerization, Silybin, Antioxidants, What&,rsquo s Known Silibinin, a major phytochemical of milk thistle seeds indicated in chronic liver disease and cirrhosis, exhibits low solubility and, consequently, low oral bioavailability. Mesoporous silica nanoparticles (MSNs) are intended for drug delivery due to their small pore size (2&,ndash 50 nm), high specific surface area, excellent biodegradability, and biocompatibility. What&,rsquo s New Synthesis of MSNs with tunable sizes and pore diameters was attained by simultaneous sol-gel reaction and free-radical polymerization. High capacity loading of silibinin in MSNs enhanced its dissolution and the preservation of its antioxidant activity in acidic gastric juice. IntroductionAmong the compounds developed in the pharmaceutical industry, about 40% show low solubility or are completely insoluble. To improve the solubility and dissolution profile of such active agents, formulation scientists need to overcome several obstacles in different phases of formulation development. 1, Over the past decades, a plethora of different organic and inorganic nanoparticles were developed for drug delivery applications. 2, These materials have a great scope in the field of medicine, since they can show better pharmacokinetic and pharmacodynamic profiles. Nowadays, drug delivery based on inorganic nanomaterials such as gold nanoparticles, iron oxide nanoparticles, quantum dots, and mesoporous silica nanoparticles (MSNs) is the focal point of great scrutiny. 3, - 5, Since the discovery of M41S in the early 1990s, MSNs with pore sizes ranging from 2 to 50 nm have attracted much attention, due to their unique properties such as high surface areas and pore volumes, uniform and tunable pore sizes, excellent biodegradability and biocompatibility, and easily modifiable surface properties. 6, Moreover, great progress has been made in the multi-functionalization design and structure control of MSNs for their potential applications such as catalysis, adsorption, separation, sensing, and drug delivery. 7, , 8, In recent years, MSNs have served as an emerging drug delivery system for various therapeutic agents. 9, Silica is classified as &,ldquo Generally Recognized as Safe&,rdquo (GRAS), by the United States Food and Drug Administration (FDA), and is widely used in cosmetic, food, and pharmaceutical industries as rheology modifiers, suspending agents, and glidants. In addition, clinical trials are still performed with targeted silica nanoparticles for an image-guided operative sentinel lymph node mapping. In contrast to solid silica nanoparticles, a mesoporous structure allows a high drug-loading capacity and a time-dependent drug release. 3, , 4, Internal silica nanochannels with large pore volumes can provide a high surface area for drug adsorption and loading, while silanol-enriched external surfaces are easily-modified and enable sustained, controlled, targeted, and stimuli-responsive drug delivery to improve therapeutic drug efficacy. 10, Shen and colleagues reported that the tunable pore size of MSNs could effectively control the loading and release kinetics of ibuprofen as a poorly water-soluble drug. 11, MSN synthesis follows a self-assembly mechanism, whereby the physical, chemical, and structural properties of the nanoparticle are controlled by reactant ratios and experimental conditions. Recent innovations in the synthesis of MSNs with controlled particle size, morphology, and porosity, along with their chemical stability, have made silica an attractive biomaterial for drug delivery. 3, , 12, , 13, Most often in the synthesis of MSNs, surfactants such as cationic cetyltrimethylammonium bromide (CTAB) are employed owing to their strong association with silica precursors, which results in MSNs with small pore sizes (about 3 nm). On the other hand, many new applications of MSNs require uniform and large pore sizes in the range of 4 to 8 nm. 3, Silibinin (SBN) is one of the structural isomers of the flavonoid silymarin, which is extracted from the milk thistle. 14, Over the past two decades, SBN has received much attention due to its anticancer and chemo-preventive actions, as well as its cholesterol-lowering, cardioprotective, and neuroprotective applications. SBN is a diastereoisomeric mixture of two flavonolignans, namely SBN A and SBN B, at a ratio of approximately 1,1. 15, In contrast to the broad therapeutic actions of SBN, its bioavailability is limited due to low aqueous solubility, low permeability across intestinal epithelial cells, extensive phase II hepatic metabolism, and rapid excretion in the bile and urine. 16, Moreover, the poor oral bioavailability of SBN is attributed to its degradation in the gastric fluid, which leads to more than a 20% degradation rate over 2 hours. 17, The low solubility and possible inactivation of SBN in the gastrointestinal tract can impede the oral bioavailability of SBN, requiring drug incorporation into an efficient delivery system. Therefore, various approaches have been proposed, including drug encapsulation into liposomes, polymeric micelles, nanoparticles, prodrugs, and microspheres. 16, It is assumed that MSNs with uniform and large pore sizes can provide a new platform for delivering poorly water-soluble phytochemicals such as SBN. For example, Cao and colleagues formulated a poorly water-soluble SBN based on polymeric porous silica nanoparticles, 18, and Ahmadi Nasab and others prepared MSNs for the delivery of curcumin (a poorly water-soluble phytochemical). 19, In light of the aforementioned research, we sought to develop well-tuned MSNs for SBN loading in high capacity with an enhanced drug dissolution rate. Unlike the conventional sol-gel method, the present MSN synthesis involves a combination of the hydrolytic condensation of tetraethyl orthosilicate (TEOS) to form silica and the simultaneous free-radical polymerization of methyl methacrylate (MMA) in a system of n-heptane/water dispersion. To optimize the delivery system, we studied the effects of the MSN pore size on the loading capacity and release profile of SBN. We also examined the impact of MSN encapsulation on preserving the antioxidant activity of SBN via the 2, 2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging assay. Materials and MethodsThe present study was performed at Shiraz University of Medical Sciences, Shiraz, Iran, in 2019. All the applied protocols were approved by the Research Ethics Committee of Shiraz University of Medical Sciences (Code, IRSUMS.REC.1397.1129). MaterialsTEOS (&,ge 99%) (Merck, Germany), CTAB (Dae-Jung, South Korea), MMA, L-lysine (97%), 4,4&,prime -Azobis (4-cyanovaleric acid) (ACVA), SBN (Sigma-Aldrich, U.S.A.), and n-heptane (Caledon, Canada) were used in the current investigation. Deionized water was produced using the MilliQ3 Integral 3 Water Purification System (Millipore, U.S.A.). All the chemicals were used as received.Synthesis of Mesoporous Silica NanoparticlesThe synthesis method shares the features of the simultaneous free-radical polymerization of methacrylate ester and the sol-gel reaction of the silica precursor at the n-heptane/water interface (figure 1A,). The process uses a basic amino acid as the catalyst, n-heptane as the organic phase component, ACVA as the initiator, and CTAB as the cationic surfactant. Briefly, 300 mg of CTAB was dissolved in 96 mL of deionized water. The mixture was purged with nitrogen gas for 45 minutes, at 70 &,deg C. After a clear solution was obtained, different amounts of n-heptane (6 and 45 mL) were added to the solution. After 15 minutes, respective amounts of 0.5 and 20 mg/mL of MMA, 66 mg of L-lysine, 3000 mg of TEOS, and 0.81 mg/mL of ACVA were added to the reaction mixture, while it was stirred at 750 rpm (table 1,). After four hours, the resulting product showed homogeneous milky colloidal dispersion. It was then cooled down to room temperature and decanted. The organic template and surfactant were removed by heating the raw products in an oven (500 &,deg C) for five hours. The final product was kept in a desiccator until use. MSN products were characterized using field emission scanning electron microscopy (FE-SEM), the Brunauer&,ndash Emmett&,ndash Teller (BET) protocol, X-ray diffraction (XRD), and dynamic light scattering (DLS).Figure 1. Schematic synthesis route is presented for the preparation of hybrid nanoparticles, composed of mesoporous silica and poly MMA. (A) FE-SEM micrographs correspond to the H1M1 (B) and H2M2 (C) preparations. MMA, Methyl methacrylate FE-SEM, Field emission scanning electron microscopy H1M1, A formulation prepared with 6 mL of n-heptane and 0.5 mg/mL of MMA H2M2, A formulation prepared with 45 mL of n-heptane and 20 mg/mL of MMASampleReagent VariationMean Particle Size (nm)Pore Size (nm)Surface Area (m2 g-1)Pore Volume (cm3g-1)Silibinin Loading Capacity (%)H0M0 (Control)without adding n-heptane and MMA106.02.401193.001.440.99H1M16 mL of n-heptane and 0.5 mg/mL of MMA44.65.60747.560.969.6H2M245 mL of n-heptane and 20 mg/mL of MMA25.97.10606.681.1013.0MSN, Mesoporous silica nanoparticles BET, Brunauer&,ndash Emmett&,ndash Teller DLS, Dynamic light scattering MMA, Methyl methacrylate H0M0, A formulation prepared without adding n-heptane and MMA H1M1, A formulation prepared with 6 mL of n-heptane and 0.5 mg/mL of MMA H2M2, A formulation prepared with 45 mL of n-heptane and 20 mg/mL of MMA |