Jeremy Steinbacher - Increased efficacy of doxorubicin delivered in multifunctional microparticles for mesothelioma therapy

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      Publication Details (including relevant citation   information): Hillegass, Jedd M., Blumen, Steven R.,   Cheng, Kai, MacPherson, Maximilian B., Alexeeva, Vlada, Lathrop,   Sherrill A., Beuschel, Stacie L., Steinbacher, Jeremy L., Butnor,   Kelly J., Ramos-Niño, Maria E., Shukla, Arti, James, Ted A.,   Weiss, Daniel J., Taatjes, Douglas J., Pass, Harvey I., Carbone,   Michele, Landry, Christopher C., Mossman, Brooke T., Int. J.   Cancer, 2011, 129 (1), pp 233-244

      Abstract: New and effective treatment strategies   are desperately needed for malignant mesothelioma (MM), an   aggressive cancer with a poor prognosis. We have shown previously   that acid-prepared mesoporous microspheres (APMS) are nontoxic   after intrapleural or intraperitoneal (IP) administration to   rodents. The purpose here was to evaluate the utility of APMS in   delivering chemotherapeutic drugs to human MM cells in vitro and   in two mouse xenograft models of MM. Uptake and release of   doxorubicin (DOX) alone or loaded in APMS (APMS-DOX) were   evaluated in MM cells. MM cell death and gene expression linked   to DNA damage/repair were also measured in vitro. In two severe   combined immunodeficient mouse xenograft models, mice received   saline, APMS, DOX or APMS-DOX injected directly into subcutaneous   (SC) MM tumors or injected IP after development of human MMs   peritoneally. Other mice received DOX intravenously (IV) via tail   vein injections. In comparison to DOX alone, APMS-DOX enhanced   intracellular uptake of DOX, MM death and expression of GADD34   and TP73. In the SC MM model, 3× weekly SC injections of APMS-DOX   or DOX alone significantly inhibited tumor volumes, and systemic   DOX administration was lethal. In mice developing IP MMs,   significant (p < 0.05) inhibition of mesenteric tumor numbers,   weight and volume was achieved using IP administration of   APMS-DOX at one-third the DOX concentration required after IP   injections of DOX alone. These results suggest APMS are   efficacious for the localized delivery of lower effective DOX   concentrations in MM and represent a novel means of treating   intracavitary tumors.

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