title: Longitudinal investigation of permeability and distribution of macromolecules in mouse malignant transformation using PET.
abstract: OBJECTIVE
  We apply positron emission tomography (PET) to elucidate changes in nanocarrier extravasation during the transition from premalignant to malignant cancer, providing insight into the use of imaging to characterize early cancerous lesions and the utility of nanoparticles in early disease.
  
  
  METHODS
  Albumin and liposomes were labeled with (64)Cu (half-life 12.7 hours), and longitudinal PET and CT imaging studies were conducted in a mouse model of ductal carcinoma in situ. A pharmacokinetic model was applied to estimate the tumor vascular volume and permeability.
  
  
  RESULTS
  From early time points characterized by disseminated hyperproliferation, the enhanced vascular permeability facilitated lesion detection. During disease progression, the vascular volume fraction increased 1.6-fold and the apparent vascular permeability to albumin and liposomes increased ∼2.5-fold to 6.6 × 10(-8) and 1.3 × 10(-8) cm/s, respectively, with the accumulation of albumin increasing earlier in the disease process. In the malignant tumor, both tracers reached similar mean intratumoral concentrations of ∼6% ID/cc but the distribution of liposomes was more heterogeneous, ranging from 1% to 18% ID/cc compared with 1% to 9% ID/cc for albumin. The tumor-to-muscle ratio was 17.9 ± 8.1 and 7.1 ± 0.5 for liposomes and albumin, respectively, indicating a more specific delivery of liposomes than with albumin.
  
  
  CONCLUSIONS
  PET imaging of radiolabeled particles, validated by confocal imaging and histology, detected the transition from premalignant to malignant lesions and effectively quantified the associated changes in vascular permeability.
authors.affiliation: Department of Physiology and Membrane Biology, University of California Davis, California, USA.
authors.forename: Cecilie B
authors.initials: CB
authors.lastname: Rygh
authors.forename: Shengping
authors.initials: S
authors.lastname: Qin
authors.forename: Jai W
authors.initials: JW
authors.lastname: Seo
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Mahakian
authors.forename: Hua
authors.initials: H
authors.lastname: Zhang
authors.forename: Roger
authors.initials: R
authors.lastname: Adamson
authors.forename: Jane Q
authors.initials: JQ
authors.lastname: Chen
authors.forename: Alexander D
authors.initials: AD
authors.lastname: Borowsky
authors.forename: Robert D
authors.initials: RD
authors.lastname: Cardiff
authors.forename: Rolf K
authors.initials: RK
authors.lastname: Reed
authors.forename: Fitz-Roy E
authors.initials: FR
authors.lastname: Curry
authors.forename: Katherine W
authors.initials: KW
authors.lastname: Ferrara
mesh_terms: D000818:Animals; D002199:Capillary Permeability; D002278:Carcinoma in Situ / Q000098:blood supply*; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D003301:Copper Radioisotopes; D018450:Disease Progression; D008081:Liposomes / Q000378:metabolism*; D008325:Mammary Neoplasms, Experimental / Q000098:blood supply*; D051379:Mice; D053758:Nanoparticles / Q000032:analysis; D049268:Positron-Emission Tomography / Q000379:methods*; D012709:Serum Albumin / Q000378:metabolism
chemical_list: D003301:Copper Radioisotopes; D008081:Liposomes; D012709:Serum Albumin