K. Adzamli et al., CHARACTERIZATION OF POLYETHYLENEGLYCOL-STABILIZED, MANGANESE-SUBSTITUTED HYDROXYLAPATITE (MNHA-PEG) - A POTENTIAL MR BLOOD-POOL AGENT, Acta radiologica, 38, 1997, pp. 73-78
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.