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

Department of Pathology and Department of Medicine, University of Vermont College of Medicine; and Department of Chemistry, University of Vermont, Burlington, Vermont

Correspondence and requests for reprints should be addressed to Dr. Brooke Mossman, University of Vermont College of Medicine, Department of Pathology, 89 Beaumont Avenue, HSRF 218, Burlington, VT 05405. E-mail: Brooke.Mossman{at}uvm.edu

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 µm diameter, 40 Å 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.

Key Words: uptake • particles • nanoparticles • lung cancer • mesothelioma

CLINICAL RELEVANCE The research presented introduces a novel method (APMS) of delivering drugs or constructs to cells in the treatment of lung and pleural diseases. Acid-prepared mesoporous spheres enter cells via a rapid, actin-dependent mechanism, which is not membrane-bound.