title: Characterization of polyethyleneglycol-stabilized, manganese-substituted hydroxylapatite (MnHA-PEG). A potential MR blood pool agent.
abstract: OBJECTIVE
  To optimize the performance (or efficacy) of a potential particulate blood pool agent for MR angiography by varying the particle size. The colloidal system under investigation was polyethylene glycol-stabilized manganese-substituted hydroxylapatite (MnHA-PEG).
  
  
  METHODS
  Several MnHA-PEG formulations were prepared using various length PEGs (MW = 140-2000). Products were characterized in vitro by dynamic light scattering (DLLS), field flow fractionation (FFF), and relaxometry; and in vivo by blood clearance kinetics in rabbits, and by analytical electron microscopy (EM).
  
  
  RESULTS
  The particle size distribution (PSD) consisted only of small particles (approximately 10-nm diameter) when approximately 40 mo1% PEG was used. At approximately 20 mo1% PEG, larger particles (approximately 100 nm), which are aggregates of the small ones, were also present. The water proton relaxation profiles of the particles in plasma were different from that of the free Mn2+. In plasma, the large aggregates were broken down into the smaller particles which were stable. Although the small particles were efficient relaxation enhancing agents, they were cleared from the blood approximately 3 times faster than the approximately 100-nm diameter aggregates, probably as a consequence of leakage into the extravascular space. Variation of PEG size had no effect on particle characteristics or on blood clearance. Analytical EM of rabbit liver specimens indicated some retention of Mn in mitochondria at the time point when Mn content of other subcellular structures returned to baseline.
  
  
  CONCLUSIONS
  DLLS and FFF are complementary techniques for sizing particulate MR contrast media. Small MnHA particles are more efficient T1-shortening agents than large ones but they are prone to leakage from the vascular space. Within the MW range explored, the length of PEG molecule had no effect on blood clearance of the MnHA particles. Larger aggregates of MnHA-PEG break down into stable small particles in plasma. Mn clears from the subcellular structures within hepatocytes within 60 min after i.v. MnHA-PEG administration except from the mitochondria in which it appears to accumulate.
authors.affiliation: Medical Imaging Division, Mallinckrodt, Inc., St. Louis, MO 63134, USA. kiadzam@mkg.com
authors.forename: K
authors.initials: K
authors.lastname: Adzamli
authors.forename: R B
authors.initials: RB
authors.lastname: Dorshow
authors.forename: M R
authors.initials: MR
authors.lastname: Hynes
authors.forename: D L
authors.initials: DL
authors.lastname: Nosco
authors.forename: M D
authors.initials: MD
authors.lastname: Adams
mesh_terms: D000818:Animals; D003287:Contrast Media / Q000032:analysis / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D004338:Drug Combinations; D004355:Drug Stability; D017886:Durapatite / Q000032:analysis / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D004577:Electron Probe Microanalysis; D008099:Liver / Q000378:metabolism; D018810:Magnetic Resonance Angiography / Q000706:statistics & numerical data; D008345:Manganese / Q000032:analysis / Q000737:chemistry* / Q000493:pharmacokinetics; D010316:Particle Size; D011092:Polyethylene Glycols / Q000032:analysis / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D011817:Rabbits; D013329:Structure-Activity Relationship; D013997:Time Factors
chemical_list: D003287:Contrast Media; D004338:Drug Combinations; D011092:Polyethylene Glycols; D008345:Manganese; D017886:Durapatite