Alfonso E. Garcia-Bennett

Better safe than sorry : understanding the toxicological properties of inorganic nanoparticles manufactured for biomedical applications

The development of nanoparticles for biomedical applications including medical imaging and drug delivery is currently undergoing a dramatic expansion. However, as the range of nanoparticle types and applications increases, it is also clear that the potential toxicities of these novel materials and the properties driving such toxic responses must also be understood. Indeed, a detailed assessment of the factors that influence the biocompatibility and/or toxicity of nanoparticles is crucial for the safe and sustainable development of the emerging nanotechnologies. This review summarizes some of the recent developments in the field of nanomedicine with particular emphasis on inorganic nanoparticles for drug delivery. The synthesis routes, physico-chemical characteristics, and cytotoxic properties of inorganic nanoparticles are thus explored and lessons learned from the toxicological investigation of three common types of engineered nanomaterials of titania, gold, and mesoporous silica are discussed. Emphasis is placed on the recognition versus non-recognition of engineered nanomaterials by the immune system, the primary surveillance system against microorganisms and particles, which, in turn, is intimately linked to the issue of targeted drug delivery using such nanomaterials as carrier systems.

Mechanisms and Kinetics for Sorption of CO2 on Bicontinuous Mesoporous Silica Modified with n-Propylamine

We studied equilibrium adsorption and uptake kinetics and identified molecular species that formed during sorption of carbon dioxide on amine-modified silica. Bicontinuous silicas (AMS-6 and MCM-48) were postsynthetically modified with (3-aminopropyl)triethoxysilane or (3-aminopropyl)methyldiethoxysilane, and amine-modified AMS-6 adsorbed more CO2 than did amine-modified MCM-48. By in situ FTIR spectroscopy, we showed that the amine groups reacted with CO2 and formed ammonium carbamate ion pairs as well as carbamic acids under both dry and moist conditions. The carbamic acid was stabilized by hydrogen bonds, and ammonium carbamate ion pairs formed preferably on sorbents with high densities of amine groups. Under dry conditions, silylpropylcarbamate formed, slowly, by condensing carbamic acid and silanol groups. The ratio of ammonium carbamate ion pairs to silylpropylcarbamate was higher for samples with high amine contents than samples with low amine contents. Bicarbonates or carbonates did not form under dry or moist conditions. The uptake of CO2 was enhanced in the presence of water, which was rationalized by the observed release of additional amine groups under these conditions and related formation of ammonium carbamate ion pairs. Distinct evidence for a fourth and irreversibly formed moiety was observed under sorption of CO2 under dry conditions. Significant amounts of physisorbed, linear CO2 were detected at relatively high partial pressures of CO2, such that they could adsorb only after the reactive amine groups were consumed.

Temperature-Induced Uptake of CO2 and Formation of Carbamates in Mesocaged Silica Modified with n-Propylamines

Adsorption-mediated CO(2) separation can reduce the cost of carbon capture and storage. The reduction in cost requires adsorbents with high capacities for CO(2) sorption and high CO(2)-over-N(2) selectivity. Amine-modified sorbents are promising candidates for carbon capture. To investigate the details of CO(2) adsorption in such materials, we studied mesocaged (cubic, Pm3n symmetry) silica adsorbents with tethered propylamines using Fourier transform infrared (FTIR) spectroscopy and volumetric uptake experiments. The degree of heterogeneity in these coatings was varied by either cosynthesizing or postsynthetically introducing the propylamine modification. In situ FTIR spectroscopy revealed the presence of both physisorbed and chemisorbed CO(2) in the materials. We present direct molecular evidence for physisorption using FTIR spectroscopy in mesoporous silica sorbents modified with propylamines. Physisorption reduced the CO(2)-over-N(2) selectivity in amine-rich sorbents. Samples with homogeneous coatings showed typical CO(2) adsorption trends and large quantities of IR-observable physisorbed CO(2). The uptake of CO(2) in mesocaged materials with heterogeneous propylamine coatings was higher at high temperatures than at low temperatures. At higher temperatures and low pressures, the postsynthetically modified materials adsorbed more CO(2) than did the extracted ones, even though the surface area after modification was clearly reduced and the coverage of primary amine groups was lower. The principal mode of CO(2) uptake in postsynthetically modified mesoporous silica was chemisorption. The chemisorbed moieties were present mainly as carbamate-ammonium ion pairs, resulting from the quantitative transformation of primary amine groups during CO(2) adsorption as established by NIR spectroscopy. The heterogeneity in the coatings promoted the formation of these ion pairs. The average propylamine-propylamine distance must be small to allow the formation of carbamate-propylammonium ion pairs.

Microsomal Glutathione Transferase 1 Protects Against Toxicity Induced by Silica Nanoparticles but Not by Zinc Oxide Nanoparticles

Microsomal glutathione transferase 1 (MGST1) is an antioxidant enzyme located predominantly in the mitochondrial outer membrane and endoplasmic reticulum and has been shown to protect cells from lipid peroxidation induced by a variety of cytostatic drugs and pro-oxidant stimuli. We hypothesized that MGST1 may also protect against nanomaterial-induced cytotoxicity through a specific effect on lipid peroxidation. We evaluated the induction of cytotoxicity and oxidative stress by TiO2, CeO2, SiO2, and ZnO in the human MCF-7 cell line with or without overexpression of MGST1. SiO2 and ZnO nanoparticles caused dose- and time-dependent toxicity, whereas no obvious cytotoxic effects were induced by nanoparticles of TiO2 and CeO2. We also noted pronounced cytotoxicity for three out of four additional SiO2 nanoparticles tested. Overexpression of MGST1 reversed the cytotoxicity of the main SiO2 nanoparticles tested and for one of the supplementary SiO2 nanoparticles but did not protect cells against ZnO-induced cytotoxic effects. The data point toward a role of lipid peroxidation in SiO2 nanoparticle-induced cell death. For ZnO nanoparticles, rapid dissolution was observed, and the subsequent interaction of Zn2+ with cellular targets is likely to contribute to the cytotoxic effects. A direct inhibition of MGST1 by Zn2+ could provide a possible explanation for the lack of protection against ZnO nanoparticles in this model. Our data also showed that SiO2 nanoparticle-induced cytotoxicity is mitigated in the presence of serum, potentially through masking of reactive surface groups by serum proteins, whereas ZnO nanoparticles were cytotoxic both in the presence and in the absence of serum.

Synthesis, toxicology and potential of ordered mesoporous materials in nanomedicine

Although ordered mesoporous silica materials have been studied for almost 20 years, their utilization within life science applications is relatively new and unexplored. An increasing number of researchers are transcending their respective fields in order to bridge the knowledge gap between materials chemistry and biotechnology, and to exploit the potential of mesoporous materials. Their intricate porosity with order in the nanoscale translates into high surface areas above 1000 m(2)/g, high selectivity for the encapsulation of biorelevant molecules as well as controlled surface chemistry. Their uses in pharmaceutics to improve drug formulation, drug bioavailability, mitigate drug toxicity and in cellular targeting, through controlled drug delivery strategies, have been shown. The incorporation of a high concentration of fluorescent and nuclear markers within their pores, whilst retaining good diffusion through their porous matrix, has shown them to be ideal candidates for sensing devices, in immunoassays such as flow cytometry and for their use in novel theranostic applications. This article aims to bring to the forefront some of the most important properties of mesoporous materials, which prove advantageous for their use in nanomedical applications and to highlight some of the potential areas into which the field may now emerge.

Efficient internalization of mesoporous silica particles of different sizes by primary human macrophages without impairment of macrophage clearance of apoptotic or antibody-opsonized target cells

Macrophage recognition and ingestion of apoptotic cell corpses, a process referred to as programmed cell clearance, is of considerable importance for the maintenance of tissue homeostasis and in the resolution of inflammation. Moreover, macrophages are the first line of defense against microorganisms and other foreign materials including particles. However, there is sparse information on the mode of uptake of engineered nanomaterials by primary macrophages. In this study, mesoporous silica particles with cubic pore geometries and covalently fluorescein-grafted particles were synthesized through a novel route, and their interactions with primary human monocyte-derived macrophages were assessed. Efficient and active internalization of mesoporous silica particles of different sizes was observed by transmission electron microscopic and flow cytometric analysis and studies using pharmacological inhibitors suggested that uptake occurred through a process of endocytosis. Moreover, uptake of silica particles was independent of serum factors. The silica particles with very high surface areas due to their porous structure did not impair cell viability or function of macrophages, including the ingestion of different classes of apoptotic or opsonized target cells. The current findings are relevant to the development of mesoporous materials for drug delivery and other biomedical applications.

Mesoporous silica-based nanomaterials for drug delivery: evaluation of structural properties associated with release rate.

We present here a study of the controlled release of amino acid-derived amphiphilic molecules from the internal pore structure of mesoporous nanoparticle drug delivery systems with different structural properties, namely cubic and hexagonal structures of various degrees of complexity. The internal pore surface of the nanomaterials presented has been functionalised with amine moieties through a one-pot method. Release profiles obtained by conductivity measurements are interpreted in terms of specific structural and textural parameters of the porous nanoparticles, such as pore geometry and connectivity. Results indicate that diffusion coefficients are lower by as much 4 orders of magnitude in two-dimensional structures in comparison to three-dimensional mesoporous solids. A fast release in turn is observed from mesocaged materials AMS-9 and AMS-8, where the presence of structural defects is thought to lead to a slightly lower diffusion coefficient in the latter. We conclude that the use of single or mixed phases of these porous systems can be utilized to provide sustained release over long time periods and expect their use in a variety of formulations.

Adjuvant Properties of Mesoporous Silica Particles Tune the Development of Effector T Cells

Alum is the most frequently used adjuvant today, primarily inducing Th2 responses. However, Th1-type responses are often desirable within immune therapy, and therefore the development of new adjuvants is greatly needed. Mesoporous silica particles with a highly ordered pore structure have properties that make them very interesting for future controlled drug delivery systems, such as controllable particle and pore size; they also have the ability to induce minor immune modulatory effects, as previously demonstrated on human-monocyte-derived dendritic cells (MDDCs). In this study, mesoporous silica particles are shown to be efficiently engulfed by MDDCs within 2 h, probably by phagocytic uptake, as seen by confocal microscopy and transmission electron microscopy. A co-culture protocol is developed to evaluate the capability of MDDCs to stimulate the development of naïve CD4(+) T cells in different directions. The method, involving ELISpot as a readout system, demonstrates that MDDCs, after exposure to mesoporous silica particles (AMS-6 and SBA-15), are capable of tuning autologous naïve T cells into different effector cells. Depending on the size and functionalization of the particles added to the cells, different cytokine patterns are detected. This suggests that mesoporous silica particles can be used as delivery vehicles with tunable adjuvant properties, which may be of importance for several medical applications, such as immune therapy and vaccination.

Aluminophosphates for CO2 Separation

The pressure-swing adsorption method for carbon dioxide capture would ideally be facilitated by adsorbents with a high capacity and a high selectivity for CO₂. Several aluminophosphates with 8-ring window apertures (AlPO₄-17, AlPO₄-18, AlPO₄-53, and AlPO₄-25) were synthesized by hydrothermal crystallization, calcined, and their CO₂ uptake and CO₂/N₂ selectivity were studied. CO₂ and N₂ uptake was determined for pressures up to 101 kPa at 273 and 293 K. Langmuir and Toth adsorption models were used to describe the adsorption isotherms. The CO₂ and N₂ uptakes strongly indicated that the squeezed 8-ring windows of certain aluminophosphates can sieve CO₂ from a CO₂ and N₂ gas mixture. Both AlPO₄-53 and AlPO₄-25 exhibited a remarkably higher uptake of CO₂ compared to N₂. The hydrophilicity of the AlPO₄ materials was investigated by means of water adsorption, and the results showed that all of the tested aluminophosphates were less water sensitive than a benchmark zeolite (13X). In particular, AlPO₄-53 and AlPO₄-25 showed a very low degree of water uptake with up to 20-30 % relative humidity. Determination of cyclic adsorption and desorption confirmed the relatively hydrophobic nature of the aluminophosphates, which render them less energy costly for the regeneration of adsorbents.

In vivo Enhancement in Bioavailability of Atazanavir in the Presence of Proton-Pump Inhibitors using Mesoporous Materials

In vivo Enhancement in Bioavailability of Atazanavir in the Presence of Proton-Pump Inhibitors using Mesoporous Materials