Increased efficacy of doxorubicin delivered in multifunctional microparticles for mesothelioma therapy.
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.
Hillegass
Jedd M
JM
Department of Pathology, University of Vermont College of Medicine, Burlington, VT 05405-0068, USA.
Blumen
Steven R
SR
Cheng
Kai
K
MacPherson
Maximilian B
MB
Alexeeva
Vlada
V
Lathrop
Sherrill A
SA
Beuschel
Stacie L
SL
Steinbacher
Jeremy L
JL
Butnor
Kelly J
KJ
Ramos-Niño
Maria E
ME
Shukla
Arti
A
James
Ted A
TA
Weiss
Daniel J
DJ
Taatjes
Douglas J
DJ
Pass
Harvey I
HI
Carbone
Michele
M
Landry
Christopher C
CC
Mossman
Brooke T
BT
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D002851:Chromatography, High Pressure Liquid; D004317:Doxorubicin / Q000008:administration & dosage / Q000627:therapeutic use*; D004337:Drug Carriers; D006801:Humans; D008654:Mesothelioma / Q000188:drug therapy*; D051379:Mice; D018613:Microscopy, Confocal; D016133:Polymerase Chain Reaction
D000970:Antineoplastic Agents; D004337:Drug Carriers; D004317:Doxorubicin