title: Magnetic resonance imaging enhancement of normal tissues and tumors using macromolecular Gd-based cascade polymer contrast agents: preclinical evaluations.
abstract: OBJECTIVE
  We sought to compare magnetic resonance imaging (MRI) enhancement using 4 novel macromolecular polyethyleneglycol (PEG)-based cascade-polymer gadolinium contrast agents (macromolecular contrast media) in normal soft tissues and a breast cancer model.
  
  
  METHODS
  Four candidate PEG cascade polymers with effective molecular weights of 74, 82, 106, and 132 kDa, respectively, and T1-relaxivities of 8.1, 9.1, 9.7, and 10.0, respectively (at 2 Tesla and 37 degrees C in HEPES buffer), initially were used to characterize liver and kidney MRI-enhancement patterns in normal Sprague-Dawley rats (n = 4-5 per contrast agent). Kinetic analysis of dynamic MRI enhancement was used in 8 nude rats bearing MDA-MB 435 breast cancers to estimate fractional plasma volume and apparent endothelial leakiness (K) in tumors and muscle.
  
  
  RESULTS
  Soft-tissue enhancement patterns followed closely the blood enhancement over the course of 30-50 minutes with estimated blood half-lives between 23 and 73 minutes, which varied with effective molecular weights. The 2 smaller compounds yielded measurable leaks in normal muscle [K = 204 and 56 microL/(min.100 cm), respectively], whereas the 2 larger molecules did not leak in muscle [K = 0 microL/(min.100 cm)]; however, MRI-assayed leakiness of tumor vessels with respect to those 2 larger macromolecular contrast media was 68 +/- 27 and 16 +/- 8 microL/(min.100 cm), respectively.
  
  
  CONCLUSIONS
  Two relatively large (effective molecular weight >82 kDa) PEG-based cascade polymer contrast agents were well-suited for MRI quantification of tissue plasma volume and for differentiating leaky cancer microvessels from nonleaky normal vessels.
authors.affiliation: Center for Pharmaceutical and Molecular Imaging, Department of Radiology, University of California, San Francisco, California 94143, USA. robert.brasch@radiology.ucsf.edu
authors.forename: Hans-Juergen
authors.initials: HJ
authors.lastname: Raatschen
authors.forename: Yanjun
authors.initials: Y
authors.lastname: Fu
authors.forename: David M
authors.initials: DM
authors.lastname: Shames
authors.forename: Michael F
authors.initials: MF
authors.lastname: Wendland
authors.forename: Robert C
authors.initials: RC
authors.lastname: Brasch
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000098:blood supply / Q000175:diagnosis* / Q000378:metabolism; D002478:Cells, Cultured; D003287:Contrast Media / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D005119:Extravasation of Diagnostic and Therapeutic Materials; D005260:Female; D019786:Gadolinium DTPA / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics; D007089:Image Enhancement / Q000379:methods*; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008279:Magnetic Resonance Imaging / Q000379:methods*; D011092:Polyethylene Glycols / Q000737:chemistry / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D012016:Reference Values
chemical_list: D003287:Contrast Media; C521505:PEG(12000)-Gen4-(Gd DTPA)8; C521506:PEG(3400)-Gen5-(Gd DTPA)13; D011092:Polyethylene Glycols; D019786:Gadolinium DTPA