title: In vivo bacteriophage peptide display to tailor pharmacokinetics of biological nanoparticles.
abstract: OBJECTIVE
  Clinical use of most radiolabeled targeting agents has been limited because of the uptake and retention in kidney and/or liver. We hypothesized that bacteriophage (phage) display could be exploited to select for peptide sequences with fast clearance and low kidney uptake with the added ability to redirect phage clearance away from the reticuloendothelial system towards the kidney possessing rapid kidney clearance.
  
  
  METHODS
  In vivo phage display was performed to identify peptides displayed on phage that were excreted rapidly into the urine of mice. A novel in vitro assay using kidney cells, developed to predict in vivo kidney retention, and in vivo pharmacokinetic analyses were performed to characterize selected peptides/phage clones.
  
  
  RESULTS
  Forty-three renal clearance clones (RCC) were identified. In vivo mixing experiments and in vitro kidney cell assays identified RCC1-02 as the lead compound. In vivo analysis of fluorescently labeled phage clones demonstrated the ability of RCC1-02 peptide to redirect the biodistribution of the large phage particle towards excretion via the kidney. Pharmacokinetic analysis of [(111)In]-radiolabeled peptides revealed that kidney retention of the control ErBB-2-avid peptide, [(111)In]DOTA-KCCYSL, at 2-h postinjection was 5.7 ± 0.7 %ID/g. In comparison, [(111)In]DOTA-RCC1-02 had kidney retention values of 1.66 ± 0.43 %ID/g, respectively.
  
  
  CONCLUSIONS
  In vivo phage display can identify phage and corresponding peptides that rapidly clear the renal system. In the future, these peptides may be used to impart favorable pharmacokinetics onto a wide range of radioimaging or therapeutic macromolecules.
authors.affiliation: Harry S. Truman Memorial Veterans Hospital, 800 Hospital Drive, Columbia, MO, 65201, USA, newtonj@missouri.edu.
authors.forename: Jessica R
authors.initials: JR
authors.lastname: Newton-Northup
authors.forename: Marie T
authors.initials: MT
authors.lastname: Dickerson
authors.forename: Senthil R
authors.initials: SR
authors.lastname: Kumar
authors.forename: George P
authors.initials: GP
authors.lastname: Smith
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Quinn
authors.forename: Susan L
authors.initials: SL
authors.lastname: Deutscher
mesh_terms: D000818:Animals; D001435:Bacteriophages / Q000737:chemistry* / Q000378:metabolism*; D002460:Cell Line; D061505:Cell Surface Display Techniques / Q000379:methods*; D007205:Indium Radioisotopes; D007668:Kidney / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D053758:Nanoparticles / Q000737:chemistry / Q000378:metabolism*; D009893:Opossums; D010455:Peptides / Q000737:chemistry / Q000493:pharmacokinetics*; D014018:Tissue Distribution; D014764:Viral Proteins / Q000737:chemistry / Q000493:pharmacokinetics
chemical_list: D007205:Indium Radioisotopes; D010455:Peptides; D014764:Viral Proteins