A multifunctional mesothelin antibody-tagged microparticle targets human mesotheliomas.
Pleural and peritoneal mesotheliomas (MMs) are chemoresistant tumors with no effective therapeutic strategies. The authors first injected multifunctional, acid-prepared mesoporous spheres (APMS), microparticles functionalized with tetraethylene glycol oligomers, intraperitoneally into rodents. Biodistribution of APMS was observed in major organs, peritoneal lavage fluid (PLF), and urine of normal mice and rats. After verification of increased mesothelin in human mesotheliomas injected into severe combined immunodeficient (SCID) mice, APMS were then functionalized with an antibody to mesothelin (APMS-MB) or bovine serum albumin (BSA), a nonspecific protein control, and tumor targeting was evaluated by inductively coupled plasma mass spectrometry and multifluorescence confocal microscopy. Some APMS were initially cleared via the urine over a 24 hr period, and small amounts were observed in liver, spleen, and kidneys at 24 hr and 6 days. Targeting with APMS-MB increased APMS uptake in mesenteric tumors at 6 days. Approximately 10% to 12% of the initially injected amount was observed in both spheroid and mesenteric MM at this time point. The data suggest that localized delivery of APMS-MB into the peritoneal cavity after encapsulation of drugs, DNA, or macromolecules is a novel therapeutic approach for MM and other tumors (ovarian and pancreatic) that overexpress mesothelin.
Department of Pathology, University of Vermont College of Medicine, Burlington, VT 05405, USA.
Sherrill L
SL
Macura
Jedd M
JM
Hillegass
Jeremy L
JL
Steinbacher
Maximilian B
MB
MacPherson
Arti
A
Shukla
Stacie L
SL
Beuschel
Timothy N
TN
Perkins
Kelly J
KJ
Butnor
Melissa J
MJ
Lathrop
Mutlay
M
Sayan
Khan
K
Hekmatyar
Douglas J
DJ
Taatjes
Risto A
RA
Kauppinen
Christopher C
CC
Landry
Brooke T
BT
Mossman
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D000943:Antigens, Differentiation / Q000276:immunology / Q000378:metabolism*; D002417:Cattle; D045744:Cell Line, Tumor; D004285:Dogs; D004337:Drug Carriers / Q000737:chemistry* / Q000493:pharmacokinetics; D005456:Fluorescent Dyes / Q000737:chemistry; D058851:GPI-Linked Proteins / Q000276:immunology / Q000378:metabolism*; D005682:Gadolinium / Q000737:chemistry; D006801:Humans; D008643:Mesentery; D000090204:Mesothelin; D008654:Mesothelioma / Q000378:metabolism*; D051379:Mice; D016513:Mice, SCID; D010316:Particle Size; D010534:Peritoneal Neoplasms / Q000378:metabolism; D051381:Rats; D012710:Serum Albumin, Bovine / Q000737:chemistry; D012822:Silicon Dioxide / Q000737:chemistry* / Q000493:pharmacokinetics; D018874:Spheroids, Cellular / Q000378:metabolism; D014018:Tissue Distribution; D014183:Transplantation, Heterologous
D000911:Antibodies, Monoclonal; D000943:Antigens, Differentiation; D004337:Drug Carriers; D005456:Fluorescent Dyes; D058851:GPI-Linked Proteins; C000715528:Msln protein, mouse; D012710:Serum Albumin, Bovine; D012822:Silicon Dioxide; D005682:Gadolinium; D000090204:Mesothelin