title: Microspheres targeted with a mesothelin antibody and loaded with doxorubicin reduce tumor volume of human mesotheliomas in xenografts.
abstract: BACKGROUND
  Malignant mesotheliomas (MMs) are chemoresistant tumors related to exposure to asbestos fibers. The long latency period of MM (30-40 yrs) and heterogeneity of tumor presentation make MM difficult to diagnose and treat at early stages. Currently approved second-line treatments following surgical resection of MMs include a combination of cisplatin or carboplatin (delivered systemically) and pemetrexed, a folate inhibitor, with or without subsequent radiation. The systemic toxicities of these treatments emphasize the need for more effective, localized treatment regimens.
  
  
  METHODS
  Acid-prepared mesoporous silica (APMS) microparticles were loaded with doxorubicin (DOX) and modified externally with a mesothelin (MB) specific antibody before repeated intraperitoneal (IP) injections into a mouse xenograft model of human peritoneal MM. The health/weight of mice, tumor volume/weight, tumor necrosis and cell proliferation were evaluated in tumor-bearing mice receiving saline, DOX high (0.2 mg/kg), DOX low (0.05 mg/kg), APMS-MB, or APMS-MB-DOX (0.05 mg/kg) in saline.
  
  
  RESULTS
  Targeted therapy (APMS-MB-DOX at 0.05 mg/kg) was more effective than DOX low (0.05 mg/kg) and less toxic than treatment with DOX high (0.2 mg/kg). It also resulted in the reduction of tumor volume without loss of animal health and weight, and significantly decreased tumor cell proliferation. High pressure liquid chromatography (HPLC) of tumor tissue confirmed that APMS-MB-DOX particles delivered DOX to target tissue.
  
  
  CONCLUSIONS
  Data suggest that targeted therapy results in greater chemotherapeutic efficacy with fewer adverse side effects than administration of DOX alone. Targeted microparticles are an attractive option for localized drug delivery.
authors.affiliation: Department of Pathology, University of Vermont College of Medicine, 89 Beaumont Avenue, Burlington, VT 05405-0068, USA. brooke.mossman@uvm.edu.
authors.forename: Sherrill L
authors.initials: SL
authors.lastname: Macura
authors.forename: Jeremy L
authors.initials: JL
authors.lastname: Steinbacher
authors.forename: Maximilian B
authors.initials: MB
authors.lastname: Macpherson
authors.forename: Melissa J
authors.initials: MJ
authors.lastname: Lathrop
authors.forename: Mutlay
authors.initials: M
authors.lastname: Sayan
authors.forename: Jedd M
authors.initials: JM
authors.lastname: Hillegass
authors.forename: Stacie L
authors.initials: SL
authors.lastname: Beuschel
authors.forename: Timothy N
authors.initials: TN
authors.lastname: Perkins
authors.forename: Page C
authors.initials: PC
authors.lastname: Spiess
authors.forename: Albert
authors.initials: A
authors.lastname: van der Vliet
authors.forename: Kelly J
authors.initials: KJ
authors.lastname: Butnor
authors.forename: Arti
authors.initials: A
authors.lastname: Shukla
authors.forename: Marilyn
authors.initials: M
authors.lastname: Wadsworth
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Landry
authors.forename: Brooke T
authors.initials: BT
authors.lastname: Mossman
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D001835:Body Weight; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000008:administration & dosage*; D016503:Drug Delivery Systems; D058851:GPI-Linked Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D007274:Injections, Intraperitoneal; D019394:Ki-67 Antigen / Q000378:metabolism; D008264:Macrophages / Q000473:pathology; D000090204:Mesothelin; D008654:Mesothelioma / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008863:Microspheres; D009336:Necrosis / Q000188:drug therapy; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D058851:GPI-Linked Proteins; D019394:Ki-67 Antigen; C000715528:Msln protein, mouse; D004317:Doxorubicin; D000090204:Mesothelin
references.citation: J Leukoc Biol. 1999 Dec;66(6):889-900
references.pmid: 10614769
references.citation: Cancer Res. 2005 Nov 1;65(21):9670-7
references.pmid: 16266986
references.citation: Eur J Cancer. 2008 Jan;44(1):46-53
references.pmid: 17945478
references.citation: Ann N Y Acad Sci. 2010 Aug;1203:7-14
references.pmid: 20716277
references.citation: Pharm Res. 2003 Sep;20(9):1337-50
references.pmid: 14567626
references.citation: Am J Clin Oncol. 2008 Feb;31(1):49-54
references.pmid: 18376228
references.citation: Arch Environ Health. 1983 Sep-Oct;38(5):261-6
references.pmid: 6651349
references.citation: Am J Respir Cell Mol Biol. 2010 Feb;42(2):133-9
references.pmid: 20068227
references.citation: Ann Surg Oncol. 2007 Feb;14(2):484-92
references.pmid: 17054002
references.citation: ACS Appl Mater Interfaces. 2010 Sep;2(9):2489-95
references.pmid: 20707315
references.citation: Clin Cancer Res. 2009 Aug 15;15(16):5274-9
references.pmid: 19671873
references.citation: Small. 2010 Dec 6;6(23):2678-82
references.pmid: 21069757
references.citation: J Environ Pathol Toxicol Oncol. 2001;20 Suppl 1:133-41
references.pmid: 11570670
references.citation: ACS Appl Mater Interfaces. 2012 Jan;4(1):235-43
references.pmid: 22117536
references.citation: Am J Surg Pathol. 2003 Feb;27(2):150-8
references.pmid: 12548160
references.citation: Int J Cancer. 2011 Jul 1;129(1):233-44
references.pmid: 20830711
references.citation: Mol Cancer Ther. 2012 Mar;11(3):517-25
references.pmid: 22351743
references.citation: Lung Cancer. 2006 Jan;51(1):53-9
references.pmid: 16169121
references.citation: Nat Rev Cancer. 2002 Jan;2(1):38-47
references.pmid: 11902584
references.citation: N Engl J Med. 1982 Jun 17;306(24):1446-55
references.pmid: 7043267
references.citation: Clin Cancer Res. 2004 Jun 15;10(12 Pt 1):3937-42
references.pmid: 15217923
references.citation: Anal Biochem. 1999 Jan 15;266(2):216-21
references.pmid: 9888978
references.citation: Curr Oncol. 2011 Apr;18(2):e84-96
references.pmid: 21505593
references.citation: J Biol Chem. 2004 Mar 5;279(10):9190-8
references.pmid: 14676194
references.citation: Clin Cancer Res. 2007 Sep 1;13(17):5144-9
references.pmid: 17785569
references.citation: Semin Oncol. 2002 Dec;29(6 Suppl 18):35-42
references.pmid: 12571809
references.citation: Cancer Res. 1987 Jun 15;47(12):3199-205
references.pmid: 3555770
references.citation: J Clin Oncol. 2009 Dec 20;27(36):6237-42
references.pmid: 19917862
references.citation: J Leukoc Biol. 2009 Nov;86(5):1065-73
references.pmid: 19741157
references.citation: Cancer Chemother Pharmacol. 2009 Apr;63(5):799-805
references.pmid: 18654746
references.citation: N Engl J Med. 1989 Jun 29;320(26):1721-30
references.pmid: 2659987
references.citation: Semin Oncol. 2002 Feb;29(1):51-61
references.pmid: 11836669
references.citation: Clin Cancer Res. 2012 Feb 1;18(3):858-68
references.pmid: 22147941
references.citation: PLoS One. 2012;7(4):e33214
references.pmid: 22485139
references.citation: Clin Cancer Res. 2010 Dec 15;16(24):6132-8
references.pmid: 21037025
references.citation: Am J Respir Cell Mol Biol. 2007 Mar;36(3):333-42
references.pmid: 17038662
references.citation: Clin Cancer Res. 2005 May 15;11(10):3814-20
references.pmid: 15897581
references.citation: J Histochem Cytochem. 2012 Sep;60(9):658-74
references.pmid: 22723527
references.citation: Cancer Metastasis Rev. 2006 Sep;25(3):315-22
references.pmid: 16967326
references.citation: Clin Cancer Res. 2005 Dec 15;11(24 Pt 1):8782-8
references.pmid: 16361566
references.citation: Am J Pathol. 2011 May;178(5):1975-85
references.pmid: 21514415
references.citation: Clin Cancer Res. 2007 Mar 1;13(5):1571-5
references.pmid: 17332303
references.citation: Semin Cancer Biol. 2006 Feb;16(1):38-52
references.pmid: 16139507
references.citation: Proc Natl Acad Sci U S A. 1996 Jan 9;93(1):136-40
references.pmid: 8552591
references.citation: Cancer Immun. 2007 Dec 19;7:20
references.pmid: 18088084
references.citation: Gastroenterol Res Pract. 2012;2012:471205
references.pmid: 22548052
references.citation: Cancer Treat Rev. 2012 Oct;38(6):605-12
references.pmid: 22104079