title: Magnitude of enhanced permeability and retention effect in tumors with different phenotypes: 89Zr-albumin as a model system.
abstract: Targeted nanoparticle-based technologies show increasing prevalence in radiotracer design. As a consequence, quantitative contribution of nonspecific accumulation in the target tissue, mainly governed by the enhanced permeability and retention (EPR) effect, becomes highly relevant for evaluating the specificity of these new agents. This study investigated the influence of different tumor phenotypes on the EPR effect, hypothesizing that a baseline level of uptake must be exceeded to visualize high and specific uptake of a targeted macromolecular radiotracer.
  
  
  METHODS
  These preliminary studies use (89)Zr-labeled mouse serum albumin ((89)Zr-desferrioxamine-mAlb) as a model radiotracer to assess uptake and retention in 3 xenograft models of human prostate cancer (CWR22rv1, DU-145, and PC-3). Experiments include PET and contrast-enhanced ultrasound imaging to assess morphology, vascularization, and radiotracer uptake; temporal ex vivo biodistribution studies to quantify radiotracer uptake over time; and histologic and autoradiographic studies to evaluate the intra- and intertumoral distribution of (89)Zr-desferrioxamine-mAlb.
  
  
  RESULTS
  Early uptake profiles show statistically significant but overall small differences in radiotracer uptake between different tumor phenotypes. By 20 h, nonspecific radiotracer uptake was found to be independent of tumor size and phenotype, reaching at least 5.0 percentage injected dose per gram in all 3 tumor models.
  
  
  CONCLUSIONS
  These studies suggest that minimal differences in tumor uptake exist at early time points, dependent on the tumor type. However, these differences equalize over time, reaching around 5.0 percentage injected dose per gram at 20 h after injection. These data provide strong support for the introduction of mandatory experimental controls of future macromolecular or nanoparticle-based drugs, particularly regarding the development of targeted radiotracers.
authors.affiliation: Program in Molecular Pharmacology and Chemistry, Memorial Sloan-Kettering Cancer Center, New York, New York.|Department of Diagnostic Radiology, University Hospital Schleswig-Holstein, Kiel, Germany.
authors.forename: Carola
authors.initials: C
authors.lastname: Heneweer
authors.affiliation: Radiochemistry Service, Department of Radiology, Memorial Sloan-Kettering Cancer Center, New York, New York.
authors.forename: Jason P
authors.initials: JP
authors.lastname: Holland
authors.affiliation: Radiochemistry Service, Department of Radiology, Memorial Sloan-Kettering Cancer Center, New York, New York.
authors.forename: Vadim
authors.initials: V
authors.lastname: Divilov
authors.affiliation: Department of Medical Physics, Memorial Sloan-Kettering Cancer Center, New York, New York.
authors.forename: Sean
authors.initials: S
authors.lastname: Carlin
authors.affiliation: Program in Molecular Pharmacology and Chemistry, Memorial Sloan-Kettering Cancer Center, New York, New York.|Radiochemistry Service, Department of Radiology, Memorial Sloan-Kettering Cancer Center, New York, New York.
authors.forename: Jason S
authors.initials: JS
authors.lastname: Lewis
mesh_terms: D000818:Animals; D001345:Autoradiography; D003676:Deferoxamine / Q000737:chemistry; D004355:Drug Stability; D006801:Humans; D007091:Image Processing, Computer-Assisted; D007502:Iron Chelating Agents / Q000737:chemistry; D008297:Male; D051379:Mice; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000473:pathology; D010539:Permeability; D049268:Positron-Emission Tomography; D011471:Prostatic Neoplasms / Q000000981:diagnostic imaging / Q000473:pathology; D011868:Radioisotopes / Q000493:pharmacokinetics; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics*; D012709:Serum Albumin / Q000493:pharmacokinetics; D014018:Tissue Distribution; D014183:Transplantation, Heterologous; D014463:Ultrasonography; D015040:Zirconium / Q000493:pharmacokinetics*
chemical_list: D007502:Iron Chelating Agents; D011868:Radioisotopes; D019275:Radiopharmaceuticals; D012709:Serum Albumin; D015040:Zirconium; D003676:Deferoxamine