Synthesis of Pore-Size-Tunable Mesoporous Silica Nanoparticles by Simultaneous Sol-Gel and Radical Polymerization to Enhance Silibinin Dissolution.

Background: Silibinin (SBN), a major active constituent of milk thistle seeds, exhibits numerous pharmacological activities. However, its oral bioavailability is low due to poor water solubility. This study aimed to develop a new synthetic approach for tuning the pore characteristics of mesoporous silica nanoparticles (MSNs) intended for the oral delivery of SBN. In addition, the effects of the pore diameter of MSNs on the loading capacity and the release profile of SBN were investigated. Methods: The present study was performed at Shiraz University of Medical Sciences, Shiraz, Iran, in 2019. This synthesis method shares the features of the simultaneous free-radical polymerization of methyl methacrylate and the sol-gel reaction of the silica precursor at the n-heptane/water interface. SBN was loaded onto MSNs, the in vitro release was determined, and the radical scavenging activities were compared between various pH values using the analysis of variance. Results: According to the Brunauer-Emmett-Teller protocol, the pore sizes were well-tuned in the range of 2 to 7 nm with a large specific surface area (600-1200 m2/g). Dynamic light scattering results showed that different volume ratios of n-heptane/water resulted in different sizes, ranging from 25 to 100 nm. Interestingly, high SBN loading (13% w/w) and the sustained release of the total drug over 12 hours were achieved in the phosphate buffer (pH=6.8). Moreover, the antioxidant activity of SBN was well preserved in acidic gastric pH. Conclusion: Well-tuned pores of MSNs provided a proper substrate, and thus, enhanced SBN loading and oral dissolution and preserved its antioxidant activity. Nevertheless, further in vitro and in vivo investigations are needed.

Therapeutic Effect of Carvacrol-loaded Albumin Nanoparticles on Arthritic Rats.

Rheumatoid arthritis (RA) is one of the most common autoimmune diseases. Carvacrol, an important natural terpenoid product in aromatic plants such as thyme, has shown anti-inflammatory effects in animal models of arthritis. However, its poor water solubility and high volatility have limited its application. In the present study in order to overcome this problem, we encapsulated carvacrol in the bovine serum albumin (BSA) nanoparticles and examined its therapeutic and immunomodulatory effects in adjuvant-induced arthritis (AIA). Carvacrol-loaded BSA nanoparticles were prepared by desolvation method. Nanoparticles had encapsulation efficiency (EE) of 67.7 ± 6.9% and loading capacity (LC) of 26.6 ± 2%. The size of particles was 148 ± 25 nm and they had monomodal distribution. After arthritis induction, the rats were treated intraperitoneally with nanoparticle for every 3 days until day 28. The treatment of the rats with 375 mg/mL carvacrol-loaded BSA nanoparticle significantly decreased clinical severity score (27.5 ± 9.8%, p = 0.008), erythrocyte sedimentation rate (33.4 ± 10%, p = 0.02), nitric oxide production (82.3 ± 2.6%, p = 0.004) and interleukin (IL)-17 gene expression (55.1 ± 8.2%, p = 0.003) compared to the untreated arthritic group. A higher reduction in inflammation severity in arthritic rats treated with carvacrol-loaded BSA in comparison to those treated with carvacrol alone was observed. In conclusion, encapsulation of carvacrol in nanoparticles reduced arthritis signs and release of NO and IL-17 inflammatory cytokine and therefore is suggested to be considered as a good approach for improving the therapeutic applications of carvacrol in RA.

Stealth Nanogels of Histinylated Poly Ethyleneimine for Sustained Delivery of Methotrexate in Collagen-Induced Arthritis Model.

PURPOSE: The study aimed to illustrate application of polycation Stealth nanogels for sustained delivery of methotrexate (MTX) in collagen induced arthritis (CIA) model in C57Bl/6 mice. METHODS: Nanogel synthesis involves metal ion coordinated self-assembly of PEGylated poly ethyleneimine (L-histidine substituted), chemical crosslinking and subsequent removal of the coordinated metal. The nanogels were characterized by TEM and DLS-zeta potential. Comparative efficacy and pharmacokinetics of the i.v. administred MTX-loaded nanogels were investigated in the CIA model. Inflammation site passive accumulation of the fluorophore-labeled nanogels was tested using in-vivo imaging of mice paw received unilateral injection of lipopolysaccharide. RESULTS: Uniform nanogels (sizes ~40 nm by TEM) were loaded with MTX (entrapment efficiency = 62% and drug loading = 54% at the MTX feeding ratio of 0.3 relative to total molar concentration of the polymer amines). The nanogels exhibited neutral surface charge and an acceptable biocompatibility in terms of albumin aggregation, hemolysis, erythrocyte aggregation and cytotoxicity. Single dose pharmacokinetics of the MTX-loaded nanogels, unlike free drug, showed a sustained plasma profile. When arthritis established as confirmed by histopathology, a remarkable decline of paw swelling and clinical scores was observed. Fluorescence intensity of the nanogels was enhanced about 2.7 folds at the inflamed than control normal ankle. CONCLUSION: Sustained delivery of MTX and preferential accumulation of the nanogels in inflamed paw might explain the superior clinical outcome of the MTX-loaded nanogels.