Tumoral distribution of long-circulating dextran-coated iron oxide nanoparticles in a rodent model.
OBJECTIVE
To investigate the accumulation and cellular uptake of long-circulating dextran-coated iron oxide (LCDIO) particles in malignant neoplasms in vivo.


METHODS
A gliosarcoma rodent model was established to determine the distribution of a model LCDIO preparation in tumors. LCDIO accumulation in tissue sections was evaluated with multichannel fluorescence microscopy with rhodaminated LCDIO, green fluorescent protein as a tumor marker, and Hoechst 33258 dye as an intravital endothelial stain. Uptake into tumor cells was corroborated with results of immunohistochemical and cell culture uptake experiments. The effect of intratumoral LCDIO uptake on magnetic resonance (MR) imaging signal intensity was evaluated with a 1.5-T superconducting magnet.


RESULTS
Tumoral accumulation of LCDIO was 0.11% +/- 0.06 of the injected dose per gram of tissue in brain tumors and was sufficient for detection at MR imaging. In tumor sections, LCDIO was preferentially localized in tumor cells (49.0% +/- 4.6) but was also taken up by macrophages in tumors (21.0% +/- 3.1) and by endothelial cells in the areas of active angiogenesis (6.5% +/- 1.4). In cell culture, LCDIO uptake was strongly correlated with growth rate of tumor cell lines.


CONCLUSIONS
Tumoral LCDIO accumulation was not negligible and helped explain MR imaging signal intensity changes observed in clinical trials. Microscopically, LCDIO accumulated predominantly in tumor cells and tumor-associated macrophages. Uptake into tumor cells appeared to be directly proportional to cellular proliferation rates.
Moore
A
A
Department of Radiology, Center for Molecular Imaging Research, Massachusetts General Hospital, Bldg 149, 13th St, 5403, Charlestown, MA 02129, USA.
Marecos
E
E
Bogdanov
A
A
Weissleder
R
R
D000818:Animals; D014408:Biomarkers, Tumor; D006690:Bisbenzimidazole; D001932:Brain Neoplasms / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology; D002455:Cell Division; D003287:Contrast Media / Q000493:pharmacokinetics*; D003911:Dextrans; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology; D005260:Female; D052203:Ferrosoferric Oxide; D005456:Fluorescent Dyes; D018316:Gliosarcoma / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology; D049452:Green Fluorescent Proteins; D006801:Humans; D007150:Immunohistochemistry; D007202:Indicators and Reagents; D007501:Iron / Q000493:pharmacokinetics*; D008164:Luminescent Proteins; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D008279:Magnetic Resonance Imaging; D058185:Magnetite Nanoparticles; D051379:Mice; D008856:Microscopy, Fluorescence; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000473:pathology; D010087:Oxides / Q000493:pharmacokinetics*; D051381:Rats; D011916:Rats, Inbred F344; D012235:Rhodamines; D013535:Suspensions; D014407:Tumor Cells, Cultured
D014408:Biomarkers, Tumor; D003287:Contrast Media; D003911:Dextrans; D005456:Fluorescent Dyes; D007202:Indicators and Reagents; D008164:Luminescent Proteins; D058185:Magnetite Nanoparticles; D010087:Oxides; D012235:Rhodamines; D013535:Suspensions; D049452:Green Fluorescent Proteins; D007501:Iron; C065507:ferumoxides; D006690:Bisbenzimidazole; D052203:Ferrosoferric Oxide