Accumulation of MRI contrast agents in malignant fibrous histiocytoma for gadolinium neutron capture therapy

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Abstract

Neutron-capture therapy with gadolinium (Gd-NCT) has therapeutic potential, especially that gadolinium is generally used as a contrast medium in magnetic resonance imaging (MRI). The accumulation of gadolinium in a human sarcoma cell line, malignant fibrosis histiocytoma (MFH) Nara-H, was visualized by the MRI system. The commercially available MRI contrast medium Gd-DTPA (Magnevist®, dimeglumine gadopentetate aqueous solution) and the biodegradable and highly gadopentetic acid (Gd-DTPA)-loaded chitosan nanoparticles (Gd-nanoCPs) were prepared as MRI contrast agents. The MFH cells were cultured and collected into three falcon tubes that were set into the 3-tesra MRI system to acquire signal intensities from each pellet by the spin echo method, and the longitudinal relaxation time (T1) was calculated. The amount of Gd in the sample was measured by inductively coupled plasma atomic emission spectrography (ICP-AES). The accumulation of gadolinium in cells treated with Gd-nanoCPs was larger than that in cells treated with Gd-DTPA. In contrast, and compared with the control, Gd-DTPA was more effective than Gd-nanoCPs in reducing T1, suggesting that the larger accumulation exerted the adverse effect of lowering the enhancement of MRI. Further studies are warranted to gain insight into the therapeutic potential of Gd-NCT.

Introduction

Neutron-capture therapy (NCT) applied to malignant tumors utilizes the nuclear neutron capture reaction of radiation-producing agents. Coupled with several elements, it was first postulated by Locher (1936). The most common element for NCT is boron (B-NCT), and the clinical outcome with the use of B-NCT has been good in patients with malignant melanoma (Mishima et al., 1989). Nonetheless, other more effective radiation-producing elements for NCT are still required. Gadolinium is also a radiation-producing element that provides the neutron capture reaction by thermal neutron irradiation. NCT with gadolinium (Gd-NCT) has several advantages over B-NCT, in that not only does gadolinium have a higher thermal neutron capture cross-section (66 times larger than that of boron) (Garber and Kinsey, 1976), but it is also used as a diagnostic agent in enhanced magnetic resonance imaging (MRI) examinations and shows promise in future Gd-NCT therapy under enhanced MRI diagnosis (Fig. 1). Although the therapeutic potential of Gd-NCT has been explored in recent years, there is no study on therapy applied to musculoskeletal tumors such as sarcoma. The future success of clinical Gd-NCT trials will depend on both the visualization of tumor cells on enhanced MRI and the selectively large accumulation of gadolinium compounds in individual tumor cells. Consequently, we used a sarcoma cell line, malignant fibrosis histiocytoma (MFH) Nara-H, in this study to determine whether the accumulation of gadolinium in the cells could be detected by the MRI system. Both the commercially available MRI contrast agent Gd-DTPA (Magnevist®, dimeglumine gadopentetate aqueous solution) and the biodegradable and highly gadopentetic acid (Gd-DTPA)-loaded chitosan nanoparticles (Gd-nanoCPs) prepared by a novel emulsion-droplet coalescence technique were used (Tokumitsu et al., 1999).

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Materials and methods

The Human sarcoma cell line, (MFH) Nara-H, was cultured in Eagle's minimum essential medium (MEM) supplemented with antibiotic–antimycotic solution and fetal bovine serum (FBS), and incubated in a humidified atmosphere of 5% CO2 in air at 37 °C. An adequate number of cells produced in the initial culture were harvested, re-seeded in three 75 cm2 cell-culture flasks at a density of 1000 cells/flask and cultured for 10 days. When the culture reached 70% confluence, the culture medium was aspirated.

Phantom model: making and visualizing the cell pellets as a tumor mass under the MRI system

Although almost 5 mm in diameter, the pellets responded well to the MRI examination. The phantom model was very easy to set, and the gadolinium signal intensity from the phantom tumor mass was successfully acquired under the commercially used MRI system (Fig. 3, Fig. 4). Although the pellets were very small, MR signal intensity was detected clearly and measured to the center of the pellets. No other studies have shown MR signals from malignant cell line mass. This phantom model also suggests

Conclusions

The accumulation of both commercially available MRI contrast agent Gd-DTPA (Magnevist®, dimeglumine gadopentetate aqueous solution) and Gd-nanoCPs was detected by MRI. Although Gd-nanoCPs demonstrated a smaller reduction of T1, their accumulation of gadolinium was larger than that of Gd-DTPA.

Acknowledgments

This work was supported by in part by Grant-in-Aid for Scientific Research 18659446 and Core-to-Core Program for “Advanced Particle Handling Technology” from Japan Society for the Promotion of Science, “Academic Frontier” Project 2006-2010 for Private Universities from Japanese Ministry of Education, Culture, Sports, Science and Technology, and Grant-in-Aid from Association for Nuclear Technology in Medicine.

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