Elsevier

Academic Radiology

Volume 11, Issue 9, September 2004, Pages 996-1004
Academic Radiology

Original investigations
Iron oxide nanoparticles as magnetic resonance contrast agent for tumor imaging via folate receptor-targeted delivery1

https://doi.org/10.1016/j.acra.2004.04.018Get rights and content

Abstract

Rationale and objective

Targeted delivery is a highly desirable strategy for diagnostic imaging because of enhanced efficacy and reduced dosage/toxicity. Receptor-targeting was used to deliver contrast-producing superparamagnetic iron oxide (IO) nanoparticle to receptor-expressing tumors for in vivo magnetic resonance (MR) imaging.

Materials and methods

Nanometer-sized, dextran-coated (maghemite) IO particles were prepared by a precipitation method. They were tethered with N-hydroxysuccinimide-folate and fluorescence isothiocyanate (FITC). For in vitro study of delivery specificity and efficiency, KB cells, a human nasopharyngeal epidermal carcinoma cell line expressing surface receptors for folic acid, were used as positive targets, and A549 cells, a human lung carcinoma cell line which lacks folate receptors, were used as negative control targets. In vivo MR images were obtained using mouse models with subcutaneous tumor xenografts grown from implanted KB cells.

Results

Internalization of nanoparticles into targeted cells only occurred when IO was conjugated to folate and when the folate receptors are available and accessible on the cells. The endocytosis was efficient and rapid, as 97.5% KB cells cultured with folate-FITC-IO showed FITC uptake after 1 hour of incubation. In in vivo MR imaging, an average intensity decrease of 38% was observed from precontrast to postcontrast images of the tumor, which was about three times the intensity decrease observed at a non-tumor-bearing muscle.

Conclusion

Successful in vivo MR imaging of folate receptor-expressing tumors targeted by IO nanoparticles was demonstrated for the first time.

Section snippets

Material preparation and characterization

All reagents used in the synthesis were commercial products and were used without further purification unless otherwise indicated. These were FeCl3.6H2O, FeCl2.4H2O, Sephacryl S-300-HR, sodium periodate, sodium bicarbonate, 1,6-diaminohexane, sodium cyanoborohydride, dycyclohexylcarbodiimide, folic acid, dimethylsulfoxide, N-hydroxysuccinimide, and fluorescein isothiocyanate, all from Sigma-Aldrich (St Louis, MO).

Starting nanometer-sized, dextran-coated IO (maghemite) particles were prepared by

Results and discussion

Preparation of folate-conjugated, dextran-coated IO nanoparticles was achieved via a scheme described in Figure 1. We used several analytical tools to determine the physical characteristics of these nanoparticles.

Figure 2 shows the particle size distributions of nanoparticles after different stages of surface conjugation. Folate-FITC-IO nanoparticles have a slightly broader distribution and larger size (26 nm) than NH2-conjugated IO nanoparticles (22 nm) based on volume average. Also shown in

Conclusion

In summary, we have prepared superparamagnetic dextran-coated IO nanoparticles with tethered folate and FITC molecules. They possess a small size (26 nm) and hydrophilicity, are capable of long circulation and targeted delivery to folate-receptor-expressing sites, and have magnetic and fluorescent properties suitable for in vivo and in vitro imaging. Successful MR imaging of folate-receptor-expressing tumors in vivo was demonstrated for the first time using these nanoparticles. These

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    Supported by grants awarded by DOE grant no. ER-61657 and National Institutes of Health grant nos. EB-00358 and CA83105.

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