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.

Lipid nanoparticles with improved biopharmaceutical attributes for tuberculosis treatment.

Tuberculosis is a topic of relevance worldwide because of the social and biological factors that triggered the disease and the economic burden on the health-care systems that imply its therapeutic treatment. Challenges to handle these issues include, among others, research on technological breakthroughs modifying the drug regimens to facilitate therapy adherence, avoid mycobacterium drug resistance, and minimize toxic side-effects. Lipid nanoparticles arise as a promising strategy in this respect as deduced from the reported scientific data. They are prepared from biodegradable and biocompatible starting materials and compared to the use of the free drugs, the entrapment of active molecules into the carriers might lead to both dose reduction and controlled delivery. Moreover, the target to the lung, the organ mainly affected by the disease, could be possible if the particle surface is modified. Although conclusive statements cannot be made considering the limited number of available research works, looking into what has been achieved up to now definitively encourages to continue investigations in this regard.

Solid lipid nanoparticles and nanostructured lipid carriers: A review emphasizing on particle structure and drug release.

Colloidal systems based on lipids have attracted attention during the last two decades as a delivery method of drugs that are poorly soluble in water. The investigations carried out have focused on the development of different formulations using a wide variety of excipients and active molecules. However, there is no consensus on the structure of the particles in these colloidal systems. This is partly due since there are few studies oriented to understand both the preferential location of the drug in the particle and the arrangement of the lipids and the stabilizing agents during the particle formation. As a contribution in this sense, in this review the most common materials and preparation methods to obtain lipid particles are presented. Also, the particle characteristics, including the shape, size and size distribution, zeta potential, drug load capacity and drug entrapment efficiency are synthesized and analyzed with the help of scientometrics tools. Emphasis has been placed on the latest advances regarding the particle structure especially as it relates to the drug release behavior. In addition to the available evidence, a model of particle structure based on the formation of the different polymorphic forms of the solid lipid because of the starting materials and the processing conditions is proposed. In general, the importance of obtaining a detailed knowledge of the structure of the lipid nanoparticles is highlighted, which is useful for the rational design of this type of nanocarriers and propose solutions to the challenges involved in their formulation.