Amorphous SiO2 nanoparticles promote cardiac dysfunction via the opening of the mitochondrial permeability transition pore in rat heart and human cardiomyocytes.

BACKGROUND: Silica nanoparticles (nanoSiO2) are promising systems that can deliver biologically active compounds to tissues such as the heart in a controllable manner. However, cardiac toxicity induced by nanoSiO2 has been recently related to abnormal calcium handling and energetic failure in cardiomyocytes. Moreover, the precise mechanisms underlying this energetic debacle remain unclear. In order to elucidate these mechanisms, this article explores the ex vivo heart function and mitochondria after exposure to nanoSiO2. RESULTS: The cumulative administration of nanoSiO2 reduced the mechanical performance index of the rat heart with a half-maximal inhibitory concentration (IC50) of 93 µg/mL, affecting the relaxation rate. In isolated mitochondria nanoSiO2 was found to be internalized, inhibiting oxidative phosphorylation and significantly reducing the mitochondrial membrane potential (ΔΨm). The mitochondrial permeability transition pore (mPTP) was also induced with an increasing dose of nanoSiO2 and partially recovered with, a potent blocker of the mPTP, Cyclosporine A (CsA). The activity of aconitase and thiol oxidation, in the adenine nucleotide translocase, were found to be reduced due to nanoSiO2 exposure, suggesting that nanoSiO2 induces the mPTP via thiol modification and ROS generation. In cardiac cells exposed to nanoSiO2, enhanced viability and reduction of H2O2 were observed after application of a specific mitochondrial antioxidant, MitoTEMPO. Concomitantly, CsA treatment in adult rat cardiac cells reduced the nanoSiO2-triggered cell death and recovered ATP production (from 32.4 to 65.4%). Additionally, we performed evaluation of the mitochondrial effect of nanoSiO2 in human cardiomyocytes. We observed a 40% inhibition of maximal oxygen consumption rate in mitochondria at 500 µg/mL. Under this condition we identified a remarkable diminution in the spare respiratory capacity. This data indicates that a reduction in the amount of extra ATP that can be produced by mitochondria during a sudden increase in energy demand. In human cardiomyocytes, increased LDH release and necrosis were found at increased doses of nanoSiO2, reaching 85 and 48%, respectively. Such deleterious effects were partially prevented by the application of CsA. Therefore, exposure to nanoSiO2 affects cardiac function via mitochondrial dysfunction through the opening of the mPTP. CONCLUSION: The aforementioned effects can be partially avoided reducing ROS or retarding the opening of the mPTP. These novel strategies which resulted in cardioprotection could be considered as potential therapies to decrease the side effects of nanoSiO2 exposure.

Physicochemical characterization, released profile, and antinociceptive activity of diphenhydraminium ibuprofenate supported on mesoporous silica.

The thermal, physical, and morphological properties of diphenhydraminium ibuprofenate ([DIP][IBU]) adsorbed onto mesoporous silica (SiO2-60 Šand SiO2-90 Å) from solution were determined. The thermal, physical, and morphological properties of [DIP][IBU] supported on silica were determined. The adsorption of [DIP][IBU] on the pores and surface of silica was proven by N2 adsorption/desorption isotherms. Additionally, release profiles were determined for all systems, and the antinociceptive activity of neat [DIP][IBU] and [DIP][IBU] supported on silica were determined. The interaction of [DIP][IBU] and silica was dependent on pore size, with the formation of a [DIP][IBU] monolayer on SiO2-60 and a multilayer on SiO2-90. The release profile was sustained and slow and dependent on the pore size of the silica, in which the smaller the pore size, the faster the release. The nociceptive evaluation showed that [DIP][IBU] presents a greater (99.21 ±â€¯0.85%) antinociceptive effect than the ibuprofen (46 ±â€¯4.3%). Additionally, [DIP][IBU] on SiO2-60 (90 ±â€¯5.8%) had a greater antinociceptive effect than on SiO2-90 (73 ±â€¯13.2%), which indicates that in vivo tests are in accordance with the in vitro experiments.

In loco retention effect of magnetic core mesoporous silica nanoparticles doped with trastuzumab as intralesional nanodrug for breast cancer.

Breast cancer is women's most common type of cancer, with a global rate of over 522,000 deaths per year. One of the main problems related to breast cancer relies in the early detection, as the specialized treatment. In this direction was developed, characterized and tested in vivo a smart delivery system, based on radiolabelled magnetic core mesoporous silica doped with trastuzumab as intralesional nanodrug for breast cancer imaging and possible therapy. The results showed that nanoparticles had a size of 58.9 ± 8.1 nm, with specific surface area of 872 m2/g and pore volume of 0.85 cm3/g with a pore diameter of 3.15 nm. The magnetic core mesoporous silica was efficiently labelled with 99mTc (97.5% ±0.8) and doped >98%. The cytotoxicity assay, demonstrated they are safe to use. The data were corroborated with the IC50 result of: 829.6 µg ± 43.2. The biodistribution showed an uptake by the tumour of 7.5% (systemic via) and 97.37% (intralesional) with less than 3% of these nanoparticles absorbed by healthy tissues. In a period 6-h post-injection, no barrier delimited by the tumour was crossed, corroborating the use as intralesional nanodrug.

Nanostructured SBA-15 host applied in ketorolac tromethamine release system.

The ordered mesoporous silica SBA-15 has been applied in studies of ketorolac tromethamine adsorption and release. The SBA-15 materials with hexagonal and regular structure were obtained using a triblock copolymer Pluronic P123 as a template and TEOS as a silica source. Ketorolac tromethamine was adsorbed into SBA-15 silica nanochannels using ethanol as solvent. The physicochemical and textural properties of SBA-15 and ketorolac tromethamine/SBA-15 were characterized by X-ray diffraction, thermogravimetric analysis, transmission electron microscopy, fourier transform infrared spectroscopy and BET surface studies. Drug release was evaluated by soaking the loaded silica mesoporous material into a solution of HCl (0.1 N) at initial time (0-2 h) and buffer pH 7 at high times at 37 °C under continuous stirring. Oral commercial Keto tablets (Dolten®) and Keto solution (Keto power) were study for the contrast. Release studies were performed in order to evaluate the required therapeutic efficacy. SBA-15 provides significant improvement in the controlled release of ketorolac tromethamine. Release profile of KETO from SBA-15/KETO and control releases.

Microparticles Containing Curcumin Solid Dispersion: Stability, Bioavailability and Anti-Inflammatory Activity.

This work aimed at improving the solubility of curcumin by the preparation of spray-dried ternary solid dispersions containing Gelucire®50/13-Aerosil® and quantifying the resulting in vivo oral bioavailability and anti-inflammatory activity. The solid dispersion containing 40% of curcumin was characterised by calorimetry, infrared spectroscopy and X-ray powder diffraction. The solubility and dissolution rate of curcumin in aqueous HCl or phosphate buffer improved up to 3600- and 7.3-fold, respectively. Accelerated stability test demonstrated that the solid dispersion was stable for 9 months. The pharmacokinetic study showed a 5.5-fold increase in curcumin in rat blood plasma when compared to unprocessed curcumin. The solid dispersion also provided enhanced anti-inflammatory activity in rat paw oedema. Finally, the solid dispersion proposed here is a promising way to enhance curcumin bioavailability at an industrial pharmaceutical perspective, since its preparation applies the spray drying, which is an easy to scale up technique. The findings herein stimulate further in vivo evaluations and clinical tests as a cancer and Alzheimer chemoprevention agent.

Synthesis, characterization, and biodistribution studies of (99m)Tc-labeled SBA-16 mesoporous silica nanoparticles.

Along with anti-cancer drug delivery researches, many efforts have been done to develop new tracers for diagnostic applications. Based on advances in molecular imaging, nanoparticles can be used to visualize, characterize and measure biological process at molecular and cellular level. Therefore, the purpose of this study was to synthesize, characterize and radiolabeled mesoporous silica nanoparticles (MSNs) for in vivo applications. The nanoparticles were synthesized, functionalized with 3-aminopropyltriethoxysilane (APTES) and then, anchored with diethylenetriaminepentaacetic acid (DTPA). Particles were physicochemical characterized by elemental analysis (CHN), thermogravimetric analysis (TGA), Fourier transform infrared spectroscopy (FTIR), and zeta potential, and were morphologically characterized by scanning electron microscopy (SEM), low-angle X-ray diffraction (XRD) and transmission electron microscopy (TEM) techniques. Results indicate that functionalization process was successfully achieved. Next, functionalized silica nanoparticles were radiolabeled with technetium-99m showing high radiochemical yields and high radiolabeled stability. These findings allow the use of the particles for in vivo applications. Biodistribution and scintigraphic images were carried out in healthy mice in order to determine the fate of the particles. Results from in vivo experiments showed high uptake by liver, as expected due to phagocytosis. However, particles also showed a significant uptake in the lungs, indicated by high lung-to-non-target tissue ratio. In summary, taking into account the great potential of these silica mesoporous structures to carry molecules this platform could be a good strategy for theranostic purposes.

Silicose: mecanismos de atuação da partícula de sílica no tecido pulmonar / Silicosis: mechanisms of action of silica particle in lung tissue

A inalação da partícula de sílica leva a um processo inflamatório exacerbado, com formação de granulomas e deposição de colágeno no parênquima pulmonar. A silicose é uma doença fibrosante, progressiva e irreversível, que leva o indivíduo a óbito devido a falência respiratória. Existem diversos mecanismos pelos quais a partícula de sílica exerce sua toxicidade, causando lesão no tecido pulmonar, sendo os principais descritos: a citotoxicidade direta, ativação de geração de oxidantes, estimulação da secreção de citocinas e quimiocinas, estimulação da secreção de fatores fibrogênicos e morte celular por apoptose. Embora a silicose seja passível de prevenção, não há um tratamento eficiente para minimizar os efeitos deletérios da mesma. Esta revisão elucida os principais mecanismos pelos quais a silicose se desenvolve, com o intuito de elaborar uma terapia eficaz.

Inhalation of silica particles leads to an exacerbated inflammatory process with formation of granulomas and collagen deposition in the lung parenchyma. Silicosis is a fibrosing disease, progressive and irreversible, leading the individual died due to respiratory failure. There are several mechanisms by which the particle silica exerts its toxicity, causing injury to the lung tissue, and the principal described: a direct cytotoxicity, activation of oxidant generation, stimulation of secretion of cytokines and chemokines, stimulating the secretion of fibrogenic factors and cell death by apoptosis. Although silicosis is preventable, no effective treatment to minimize the deleterious effects of same. This review elucidates the major mechanisms by which silicosis develops, in order to develop an effective therapy

Biodistribution of nanoparticles: initial considerations.

Nanotechnology is attracting increasing attention worldwide. This study was made use of modern technology to decipher most of the intriguing biological aspects of nanoparticles. Labeling with technetium-99m ((99m)Tc) of six nanoparticles using different compositions and formulations, as well as complete biodistribution studies in mice was done. The results showed that the behaviors of nanoparticles were very different from each other. Mesoporous silica showed a high affinity for lung tissue, whereas polymeric nanoparticles were rapidly recognized and metabolized by the liver. The six nanoparticles showed different renal clearance times, suggesting that their area mechanisms of action were related to interaction and solubility. The labeling process in all samples showed similar results (all >99%). Biodistribution was demonstrated to be important for the study of nanoparticles, and could be used to predict the possible mechanism of action of nanoparticles.