CHARACTERIZATION OF POLYETHYLENEGLYCOL-STABILIZED, MANGANESE-SUBSTITUTED HYDROXYLAPATITE (MNHA-PEG) - A POTENTIAL MR BLOOD-POOL AGENT

Purpose: To optimize the performance (or efficacy) of a potential part iculate blood pool agent for MR angiography by varying the particle si ze. The colloidal system under investigation was polyethylene glycol-s tabilized manganese-substituted hydroxylapatite (MnHA-PEG). Material a nd Methods: Several MnHA-PEG formulations were prepared using various length PEGs (MW = 140-2 000). Products were characterized in vitro by dynamic Light scattering (DLLS), field flow fractionation (FFF), and r elaxometry; and in vivo by blood clearance kinetics in rabbits, and by analytical electron microscopy (EM). Results: The particle size distr ibution (PSD) consisted only of small particles (similar to 10-nm diam eter) when similar to 40 mol% PEG was used. At similar to 20 mol% PEG, larger particles (similar to 100 nm), which are aggregates of the sma ll ones, were also present. The water proton relaxation profiles of th e particles in plasma were different from that of the free Mn2+. In pl asma, the large aggregates were broken down into the smaller particles which were stable. Although the small particles were efficient relaxa tion enhancing agents, they were cleared from the blood similar to 3 t imes faster than the similar to 100-nm diameter aggregates, probably a s a consequence of leakage into the extravascular space. Variation of PEG size had no effect on particle characteristics or on blood clearan ce. Analytical EM of rabbit liver specimens indicated some retention o f Mn in mitochondria at the time point when Mn content of other subcel lular structures returned to baseline. Conclusion: DLLS and FFF are co mplementary techniques for sizing particulate MR contrast media. Small MnHA particles are more efficient T1-shortening agents than large one s 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 cle arance 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 admin istration except from the mitochondria in which it appears to accumula te.