Abstract 4398: Methotrexate derivative with intrinsic magnetism
Authors: UMEMURA MASANARI , Katsumata Mayumi , Sato Itaru , Nagasako Akane , Aoyama Haruki , Makino Ayako , Ohtake Makoto , Oda Kayoko , Matsuo Kosuke , Eguchi Haruki , Ishikawa Yoshihiro 
Published: August 2015

Background: We previously reported the generation of a novel paclitaxel derivative with intrinsic magnetism. Similarly, we have synthesized a novel derivative of methotrexate, a conventional drug for cancer and rheumatic diseases, with intrinsic magnetism (M-MTX). MTX is widely used in clinical treatments, however various severe side effects such as renal, hepatic, and pulmonary toxicities or bone marrow suppression have been reported. This is a single methotrexate compound with intrinsic magnetism and is not a methotrexate encapsulated in micelle with magnetic particles. The magnetic property contributes to unique features. 1) It can be attracted by a magnet, resulting in reduction of the side effects. 2) It can be visualized by magnetic resonance imaging (MRI), suggesting that we can identify the localization of drug and quantify the amount of this drug. In this study, we have examined whether M-MTX has both the magnetic and the anti-cancer property with similar efficacy to commercial available methotrexate.

Materials & Methods: The magnetic property of M-MTX was measured by Electron Spin Resonance (ESR) and Superconducting Quantum Interference Device (SQUID). MCF7, breast cancer cells were obtained from RIKEN Bioresource center in this study. Cell proliferation was assessed by a commercially available kit, XTT Cell Proliferation Assay Kit (ATCC). Apoptotic cells were stained with APC Annexin V and 7-AAD, and measured by fluorescence activated cell sorting (FACS), to evaluate early and late apoptosis. The intracellular ROS level was then measured using a fluorescent dye, 2′,7′-dichlorofluorescein diacetate (DCFH-DA; Sigma, Japan)

Results: M-MTX was easily attracted by a neodium magnet. Plots of magnetization versus magnetic field revealed that the magnetized methotrexate exhibits spontaneous magnetization in SQUID. ESR also showed that M-MTX has an intrinsic magnetism. Furthermore, M-MTX inhibited cell proliferation and induced cellular apoptosis in MCF7 cell lines in a dose-dependent manner. M-MTX also increased reactive oxygen species (ROS) generation, suggesting that M-MTX might retained the original anti-cancer property.

Conclusion: M-MTX may provide us a new strategy for cancer therapy, i.e., chemotherapy with magnetic drug delivery with a single agent. These results also suggested that various conventional anti-cancer drugs might be similarly magnetized, leading to novel drug developments in future cancer chemotherapy and other treatments.

Note: This abstract was not presented at the meeting.

Citation Format: MASANARI UMEMURA, Mayumi Katsumata, Itaru Sato, Akane Nagasako, Haruki Aoyama, Ayako Makino, Makoto Ohtake, Kayoko Oda, Kosuke Matsuo, Haruki Eguchi, Yoshihiro Ishikawa. Methotrexate derivative with intrinsic magnetism. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4398. doi:10.1158/1538-7445.AM2015-4398