Factors regulating macrophage endocytosis of nanoparticles: implications for targeted magnetic resonance plaque imaging.
BACKGROUND
The presence of activated macrophages (Mphi) is an early and consistent marker of the inflammatory nature of atherosclerotic disease. Dextran-coated superparamagnetic iron oxide particles (SPIO) are avidly endocytosed. These particles have a strong effect on magnetic resonance signal and have been proposed as a non-invasive probe for the presence of early non-occlusive atherosclerotic disease. We describe the extent to which endogenous and exogenous factors regulate Mphi uptake of SPIO particles.


RESULTS
Cultured murine Mphi-like cells (J744A.1) incubated with SPIO (0, 11.2, 112.0 and 1120 microg Fe/ml) demonstrated significantly reduced SPIO uptake when pretreated with lovastatin to 61% (P < 0.001) and 43% (P = 0.02) of control at 1.0 microM and 17.5 microM lovastatin respectively. Interferon-gamma (IFN-gamma, 1000 U/ml) increased SPIO uptake to 163% of control, P < 0.05. Interleukin-4 (IL-4, 40 ng/ml) also increased uptake (178% of control, P < 0.04). In cells incubated with SPIO in the absence of serum proteins, SPIO uptake fell to 57% of control (P < 0.001).


CONCLUSIONS
Uptake of SPIO by activated Mphi is regulated by endogenous cytokines and serum components as well and exogenous lovastatin. Thus, MRI signal changes after SPIO administration may reflect Mphi phagocytic capacity as well as Mphi presence.
Rogers
Walter J
WJ
Department of Radiology, University of Virginia Health System, 409 Lee Street Box 801339, Charlottesville, VA 22908, USA. wjr4n@virginia.edu
Basu
Partha
P
D000818:Animals; D001161:Arteriosclerosis / Q000175:diagnosis; D001798:Blood Proteins / Q000494:pharmacology*; D045744:Cell Line, Tumor; D003287:Contrast Media; D016207:Cytokines / Q000494:pharmacology*; D003911:Dextrans; D004305:Dose-Response Relationship, Drug; D042241:Early Diagnosis; D004705:Endocytosis / Q000187:drug effects*; D052203:Ferrosoferric Oxide; D007371:Interferon-gamma / Q000494:pharmacology; D015847:Interleukin-4 / Q000494:pharmacology; D007501:Iron / Q000493:pharmacokinetics*; D008148:Lovastatin / Q000008:administration & dosage / Q000494:pharmacology*; D008264:Macrophages / Q000378:metabolism*; D008279:Magnetic Resonance Imaging; D058185:Magnetite Nanoparticles; D051379:Mice; D049329:Nanostructures; D010087:Oxides / Q000493:pharmacokinetics*
D001798:Blood Proteins; D003287:Contrast Media; D016207:Cytokines; D003911:Dextrans; D058185:Magnetite Nanoparticles; D010087:Oxides; D015847:Interleukin-4; D007371:Interferon-gamma; D008148:Lovastatin; D007501:Iron; C065507:ferumoxides; D052203:Ferrosoferric Oxide