title: Evaluation of a novel macromolecular cascade-polymer contrast medium for dynamic contrast-enhanced MRI monitoring of antiangiogenic bevacizumab therapy in a human melanoma model.
abstract: OBJECTIVE
  To assess the applicability of a novel macromolecular polyethylene glycol (PEG)-core gadolinium contrast agent for monitoring early antiangiogenic effects of bevacizumab using dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI).
  
  
  METHODS
  Athymic rats (n = 26) implanted with subcutaneous human melanoma xenografts underwent DCE-MRI at 2.0 T using two different macromolecular contrast agents. The PEG core cascade polymer PEG12,000-Gen4-(Gd-DOTA)16, designed for clinical development, was compared to the prototype, animal-only, macromolecular contrast medium (MMCM) albumin-(Gd-DTPA)35. The treatment (n = 13) and control (n = 13) group was imaged at baseline and 24 hours after a single dose of bevacizumab (1 mg) or saline to quantitatively assess the endothelial-surface permeability constant (K(PS), μL⋅min⋅100 cm(3)) and the fractional plasma volume (fPV,%), using a two-compartment kinetic model.
  
  
  RESULTS
  Mean K(PS) values, assessed with PEG12,000-Gen4-(Gd-DOTA)16, declined significantly (P < .05) from 29.5 ± 10 μL⋅min⋅100 cm(3) to 10.4 ± 7.8 μL⋅min⋅100 cm(3) by 24 hours after a single dose of bevacizumab. In parallel, K(PS) values quantified using the prototype MMCM albumin-(Gd-DTPA)35 showed an analogous, significant decline (P < .05) in the therapy group. No significant effects were detected on tumor vascularity or on microcirculatory parameters in the control group between the baseline and the follow-up scan at 24 hours.
  
  
  CONCLUSIONS
  DCE-MRI enhanced with the novel MMCM PEG12,000-Gen4-(Gd-DOTA)16 was able to monitor the effects of bevacizumab on melanoma xenografts within 24 hours of a single application, validated by the prototype, animal-only albumin-(Gd-DTPA)35. PEG12,000-Gen4-(Gd-DOTA)16 may be a promising candidate for further clinical development as a macromolecular blood pool contrast MRI agent.
authors.affiliation: Center for Pharmaceutical and Molecular Imaging, Department of Radiology, University of California San Francisco, San Francisco, California; Department of Clinical Radiology, Laboratory for Experimental Radiology, University Hospitals Munich, Campus Grosshadern, Marchioninistrasse 15, 81377 Munich, Germany. Electronic address: Clemens.Cyran@med.lmu.de.
authors.forename: Clemens C
authors.initials: CC
authors.lastname: Cyran
authors.forename: Yanjun
authors.initials: Y
authors.lastname: Fu
authors.forename: Victor
authors.initials: V
authors.lastname: Rogut
authors.forename: Bundit
authors.initials: B
authors.lastname: Chaopathomkul
authors.forename: Michael F
authors.initials: MF
authors.lastname: Wendland
authors.forename: David M
authors.initials: DM
authors.lastname: Shames
authors.forename: Robert C
authors.initials: RC
authors.lastname: Brasch
mesh_terms: D020533:Angiogenesis Inhibitors / Q000627:therapeutic use; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use; D000068258:Bevacizumab; D002214:Capsules / Q000737:chemistry; D045744:Cell Line, Tumor; D003287:Contrast Media / Q000138:chemical synthesis; D016903:Drug Monitoring / Q000379:methods; D006571:Heterocyclic Compounds / Q000737:chemistry; D006801:Humans; D046911:Macromolecular Substances / Q000138:chemical synthesis; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008545:Melanoma / Q000150:complications / Q000188:drug therapy* / Q000473:pathology*; D009389:Neovascularization, Pathologic / Q000150:complications / Q000188:drug therapy* / Q000473:pathology*; D009942:Organometallic Compounds / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry; D051381:Rats; D011923:Rats, Nude; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D016896:Treatment Outcome
chemical_list: D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D002214:Capsules; D003287:Contrast Media; D006571:Heterocyclic Compounds; D046911:Macromolecular Substances; D009942:Organometallic Compounds; D000068258:Bevacizumab; D011092:Polyethylene Glycols; C050823:gadolinium 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetate
keywords: Dynamic MRI; anti-angiogenesis effect; bevacizumab; gadolinium polyethylene glycol polymer contrast agent; human melanoma xenograft
references.citation: Future Oncol. 2011 May;7(5):669-77
references.pmid: 21568682
references.citation: Magn Reson Med. 1993 May;29(5):616-22
references.pmid: 8505897
references.citation: Bioconjug Chem. 2006 Jul-Aug;17(4):1043-56
references.pmid: 16848414
references.citation: Cancer Discov. 2011 Dec;1(7):OF1-2
references.pmid: 22586694
references.citation: J Nucl Med. 2009 May;50 Suppl 1:122S-50S
references.pmid: 19403881
references.citation: J Magn Reson Imaging. 2008 Mar;27(3):581-9
references.pmid: 18219614
references.citation: Pharm Res. 2007 Jun;24(6):1172-85
references.pmid: 17385018
references.citation: Invest Radiol. 2006 Dec;41(12):860-7
references.pmid: 17099424
references.citation: Front Biosci (Landmark Ed). 2011 Jan 01;16:803-14
references.pmid: 21196204
references.citation: J Magn Reson Imaging. 2000 Dec;12(6):991-1003
references.pmid: 11105041
references.citation: Acad Radiol. 1996 Aug;3 Suppl 2:S282-5
references.pmid: 8796581
references.citation: J Clin Oncol. 2006 Jun 1;24(16):2505-12
references.pmid: 16636341
references.citation: Drug Saf. 2012 Jan 1;35(1):15-25
references.pmid: 22136182
references.citation: Invest Radiol. 1987 Aug;22(8):665-71
references.pmid: 3667174
references.citation: Contrast Media Mol Imaging. 2013 May-Jun;8(3):220-8
references.pmid: 23606425
references.citation: Invest Radiol. 2005 Jun;40(6):349-54
references.pmid: 15905721
references.citation: J Exp Med. 1991 Nov 1;174(5):1275-8
references.pmid: 1940805
references.citation: Eur J Radiol. 2012 May;81(5):891-6
references.pmid: 21889860
references.citation: AJR Am J Roentgenol. 2012 Feb;198(2):384-91
references.pmid: 22268182
references.citation: Eur Radiol. 2009 Jan;19(1):121-31
references.pmid: 18665367
references.citation: Biomacromolecules. 2007 May;8(5):1519-29
references.pmid: 17402781
references.citation: J Magn Reson Imaging. 2004 Jul;20(1):138-44
references.pmid: 15221819
references.citation: Radiology. 2001 Mar;218(3):670-8
references.pmid: 11230638
references.citation: Bioconjug Chem. 2012 Nov 21;23(11):2291-9
references.pmid: 23035964
references.citation: J Magn Reson Imaging. 1997 Jan-Feb;7(1):68-74
references.pmid: 9039595
references.citation: Radiology. 2007 Apr;243(1):105-11
references.pmid: 17329684
references.citation: Radiology. 1998 May;207(2):539-44
references.pmid: 9577507
references.citation: Neoplasia. 2004 May-Jun;6(3):213-23
references.pmid: 15153333
references.citation: Cancer Invest. 1998;16(4):225-30
references.pmid: 9589031
references.citation: Acta Radiol. 2010 Sep;51(7):751-67
references.pmid: 20590365