Unique Uptake of Acid-Prepared Mesoporous Spheres by Lung Epithelial and Mesothelioma Cells

Abstract

Lung cancers, malignant mesotheliomas (MM), and fibrosis are devastating diseases with limited treatment strategies, in part due to poorly-effective drug delivery to affected areas of lung. We hypothesized that acid-prepared mesoporous spheres (APMS) (1-2 microm diameter, 40 A pore size) might be effective vehicles for pulmonary chemotherapeutic drug delivery. To assess this, APMS, chemically modified with different surface molecules (lipid, a linker having a terminal amine group, a thiol group, or tetraethylene glycol [TEG]), were evaluated for uptake and possible cytotoxic effects after in vitro administration to murine alveolar epithelial Type II (C10) and human mesothelioma (MM) cells and after intrapleural or intranasal administration to C57Bl/6 mice. APMS coated with TEG (APMS-TEG) were most efficiently taken up by C10 and MM cells. The mechanism of cell uptake was rapid, actin-dependent, and did not involve clathrin- or caveolae-mediated mechanisms nor fusion of membrane-bound APMS with lysosomes. When injected intrapleurally in mice, APMS-TEG were taken up by both CD45-positive and -negative cells of the diaphragm, lung, and spleen, whereas APMS administered by the intranasal route were predominantly in lung epithelial cells and alveolar macrophages. After intrapleural or intranasal administration, APMS were nonimmunogenic and nontoxic as evaluated by differential cell counts and lactate dehydrogenase levels in bronchoalveolar and pleural lavage fluids. In the treatment of lung and pleural diseases, APMS-TEG may be useful tools to deliver chemotherapeutic drugs or molecular constructs.

Alterations in Gene Expression in Human Mesothelial Cells Correlate with Mineral Pathogenicity

“…The surface area of asbestos fibers and particles was measured using nitrogen gas sorption analysis to allow computation of identical amounts of surface areas of particulates to be added to cells. Fiber and particle size dimensions were determined by scanning electron microscopy (SEM) as described previously (16). In addition, talc was examined using field emission scanning electron microscopy (FESEM) and transmission electron microscopy (TEM).…”

“…Cells were grown on Thermonox plastic cover slips (Nalge Nunc International, Naperville, IL), exposed to particulates for 24 hours, and then processed for SEM as described previously (16). After samples were critical point-dried, they were mounted on aluminum specimen stubs and dried before being sputter-coated with gold and palladium in a Polaron sputter coater (Model 5100; Quorum Technologies, Guelph, ON, Canada) and examined on a JSM 6060 scanning electron microscope (JEOL USA, Inc., Peabody, MA).…”

Ordered mesoporous silicates as matrices for controlled release of drugs

“…In vitro cytotoxicity studies suggest that these materials exhibit low toxicity at low concentrations (36)(37)(38)(39)(40)(41) but the toxicity appears to increase at higher concentrations (39). Small amounts of SBA and MCM mesoporous particles have shown little toxicity in in vivo studies (39,42). A good knowledge of the chemistry of mesoporous silicates and their behavior in the human body as well as toxicity tests are an essential requirement for any biomedical applications of these materials.…”

In vitro biocompatibility of calcined mesoporous silica particles and fetal blood cells

“…For instance, a recent in vivo study suggested efficient uptake and biocompatibility of mesoporous silica nanospheres in murine pneumatocytes and mesothelioma cells. 20 In contrast, toxicity of MCM-41 and SBA-15 in mesothelial cells has been reported, eg, intraperitoneal and intravenous injections of either particle produced pulmonary thromboembolic events. 21 Differences in dose, surface area, surface charge, pore diameter, residual reagents, and templates on the materials, as well as route of administration, have all been implicated as potential causes of conflicting results.…”

“…For instance, differences in cellular bioenergetics, cellular uptake, distribution, and other adverse effects have been observed with a variety of mesoporous silica particles prepared by different synthetic methods. 4,15,17,20,21 In addition, the methods used for removing organic templates from mesoporous materials may produce mesoporous materials with different properties, as was discovered recently. 22 Generally, two methods are used to remove the organic templates from these mesoporous materials, ie, high-temperature calcination in air or simple solventwashing (extraction).…”