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We previously identified a novel nanomagnetic particle, N,N'-bis(salicylidene)ethylenediamine iron [Fe(Salen)]. Fe(Salen) not only shows antitumor effects but also magnetic properties. We found that Fe(Salen) can be used for magnet-guided drug delivery and visualization of accumulated drug by magnetic resonance imaging (MRI) because of its magnetism. In addition, Fe(Salen) can generate heat by itself when exposed to an alternating current magnetic field (AMF), resulting in a hyperthermia effect. Herein, we partly elucidated the antitumor mechanism of Fe(Salen) and carried out an i.v. repeated dose toxicity study to decide the therapeutic amount. Furthermore, we evaluated the antitumor effect of selective intra-arterial injection or i.v. injection of Fe(Salen) by catheter and the hyperthermia effect of Fe(Salen) when exposed to AMF in vivo. We used a rabbit model grafted with VX2 cells (rabbit squamous cell carcinoma) on the right leg. Intra-arterial injection of Fe(Salen) showed a greater antitumor effect than did i.v. injection. The combination of Fe(Salen) intra-arterial injection and AMF exposure showed a greater antitumor effect than did either Fe(Salen) or methotrexate (MTX) without AMF exposure, suggesting that AMF exposure greatly enhanced the antitumor effect of Fe(Salen) by arterial injection by catheter. This is the first report that the effectiveness of Fe(Salen) was evaluated in the point of administration route; that is, selective intra-arterial injection by catheter. Taken together, these results indicate a new administration route; that is, selective arterial injection of Fe(Salen) by catheter, and the development of a new strategy of simultaneous hyperthermia-chemotherapy in the future.

We previously reported the efficacy of anti‐cancer therapy with hyperthermia using an alternating magnetic field (AMF) and a magnetic compound. In the course of the study, unexpectedly, we found that an AMF enhances the cytotoxicity of Compound C, an activated protein kinase (AMPK) inhibitor, although this compound is not magnetic. Therefore, we examined the cellular mechanism of AMF‐induced cytotoxicity of Compound C in cultured human glioblastoma (GB) cells. An AMF (280 kHz, 250 Arms) for 30 minutes significantly enhanced the cytotoxicity of Compound C and promoted apoptosis towards several human GB cell lines in vitro. The AMF also increased Compound C‐induced cell‐cycle arrest of GB cells at the G2 phase and, thus, inhibited cell proliferation. The AMF increased Compound C‐induced reactive oxygen species production. Furthermore, the AMF decreased ERK phosphorylation in the presence of Compound C and suppressed the protective autophagy induced by this compound. The application of an AMF in cancer chemotherapy may be a simple and promising method, which might reduce the doses of drugs used in future cancer treatment and, therefore, the associated side effects.

Background Paragangliomas are generally benign, slow-growing tumors. However, approximately 10%–20% are malignant, characterized by distant metastasis. Recently, a germ line mutation in succinate dehydrogenase B subunit (SDHB) has been shown to be associated with malignant behavior in paraganglioma. Here we present a case of SDHB-negative malignant paraganglioma of the jugular foramen with a pseudohypoxic microenvironment and unique imaging features on [18F]-fluoro-2-deoxy- d -glucose positron emission tomography ([18F]-FDG PET), and discuss the significance of SDHB immunohistochemistry and the potential of [18F]-FDG PET for clinical management. Case Description A 55-year-old woman was diagnosed with jugular foramen paraganglioma. Initial surgical resection was performed; however, follow-up [18F]-FDG PET indicated multiple uptake regions throughout the body. Biopsies for multiple recurrent lesions revealed consistent pathological features, suggesting distant metastasis. Immunohistochemical analysis revealed a lack of SDHB immunostaining in all specimens. Pseudohypoxic markers, including hypoxia-inducible factor-1α and downstream glycolysis enzymes, were strongly expressed. [18F]-FDG PET demonstrated increased uptake in the lesions, and the patient died 3 years after initial metastasis. Conclusion In patients with head and neck paraganglioma without SDHB expression, close follow-up should be considered because of the risk for metastasis. In such cases, [18F]-FDG PET might be useful for detecting metastasis due to atypical accumulation from pseudohypoxia-induced glycolysis.

Iron-salen, i.e., μ-oxo-N,N′-bis(salicylidene)ethylenediamine iron (Fe(Salen)) was a recently identified as a new anti-cancer compound with intrinsic magnetic properties. Chelation therapy has been widely used in management of metallic poisoning, because an administration of agents that bind metals can prevent potential lethal effects of particular metal. In this study, we confirmed the therapeutic effect of deferoxamine mesylate (DFO) chelation against Fe(Salen) as part of the chelator antidote efficacy. DFO administration resulted in reduced cytotoxicity and ROS generation by Fe(Salen) in cancer cells. DFO (25 mg/kg) reduced the onset of Fe(Salen) (25 mg/kg)-induced acute liver and renal dysfunction. DFO (300 mg/kg) improves survival rate after systematic injection of a fatal dose of Fe(Salen) (200 mg/kg) in mice. DFO enables the use of higher Fe(Salen) doses to treat progressive states of cancer, and it also appears to decrease the acute side effects of Fe(Salen). This makes DFO a potential antidote candidate for Fe(Salen)-based cancer treatments, and this novel strategy could be widely used in minimally-invasive clinical settings.

BACKGROUND AND PURPOSE: (62)Cu-diacetyl-bis(N(4)-methylthiosemicarbazone) was developed as a hypoxic radiotracer in PET. We compared imaging features among MR imaging and (62)Cu-diacetyl-bis(N(4)-methylthiosemicarbazone)-PET, FDG-PET, and L-methyl-[(11)C]methionine)-PET in gliomas. MATERIALS AND METHODS: We enrolled 23 patients who underwent (62)Cu-diacetyl-bis(N(4)-methylthiosemicarbazone)-PET and FDG-PET and 19 (82.6%) who underwent L-methyl-[(11)C]methionine)–PET, with all 23 patients undergoing surgery and their diagnosis being then confirmed by histologic examination as a glioma. Semiquantitative and volumetric analysis were used for the comparison. RESULTS: There were 10 newly diagnosed glioblastoma multiforme and 13 nonglioblastoma multiforme (grades II and III), including 4 recurrences without any adjuvant treatment. The maximum standardized uptake value and tumor/background ratios of (62)Cu-diacetyl-bis(N(4)-methylthiosemicarbazone), as well as L-methyl-[(11)C]methionine, were significantly higher in glioblastoma multiforme than in nonglioblastoma multiforme (P = .03 and P = .03, respectively); no significant differences were observed on FDG. At a tumor/background ratio cutoff threshold of 1.9, (62)Cu-diacetyl-bis(N(4)-methylthiosemicarbazone) was most predictive of glioblastoma multiforme, with 90.0% sensitivity and 76.9% specificity. The positive and negative predictive values, respectively, for glioblastoma multiforme were 75.0% and 85.7% on (62)Cu-diacetyl-bis(N(4)-methylthiosemicarbazone), 83.3% and 60.0% on L-methyl-[(11)C]methionine, and 72.7% and 75.0% on MR imaging. In glioblastoma multiforme, volumetric analysis demonstrated that (62)Cu-diacetyl-bis(N(4)-methylthiosemicarbazone) uptake had significant correlations with FDG (r = 0.68, P = .03) and L-methyl-[(11)C]methionine (r = 0.87, P = .03). However, the (62)Cu-diacetyl-bis(N(4)-methylthiosemicarbazone)–active region was heterogeneously distributed in 50.0% (5/10) of FDG-active and 0% (0/6) of L-methyl-[(11)C]methionine)–active regions. CONCLUSIONS: (62)Cu-diacetyl-bis(N(4)-methylthiosemicarbazone) may be a practical radiotracer in the prediction of glioblastoma multiforme. In addition to FDG-PET, L-methyl-[(11)C]methionine)–PET, and MR imaging, (62)Cu-diacetyl-bis(N(4)-methylthiosemicarbazone)-PET may provide intratumoral hypoxic information useful in establishing targeted therapeutic strategies for patients with glioblastoma multiforme.

Purpose Semiquantitative analysis of thallium-201 chloride single photon emission computed tomography ( 201 Tl SPECT) was evaluated for the discrimination between recurrent brain tumor and delayed radiation necrosis after gamma knife surgery (GKS) for metastatic brain tumors and high-grade gliomas. Methods and Materials The medical records were reviewed of 75 patients, including 48 patients with metastatic brain tumor and 27 patients with high-grade glioma who underwent GKS in our institution, and had suspected tumor recurrence or radiation necrosis on follow-up neuroimaging and deteriorating clinical status after GKS. Analysis of 201 Tl SPECT data used the early ratio (ER) and the delayed ratio (DR) calculated as tumor/normal average counts on the early and delayed images, and the retention index (RI) as the ratio of DR to ER. Results A total of 107 tumors were analyzed with 201 Tl SPECT. Nineteen lesions were removed surgically and histological diagnoses established, and the other lesions were evaluated with follow-up clinical and neuroimaging examinations after GKS. The final diagnosis was considered to be recurrent tumor in 65 lesions and radiation necrosis in 42 lesions. Semiquantitative analysis demonstrated significant differences in DR ( P =.002) and RI ( P P =.372), between the tumor recurrence and radiation necrosis groups, and no significant differences between metastatic brain tumors and high-grade gliomas in all indices ( P =.926 for ER, P =.263 for DR, and P =.826 for RI). Receiver operating characteristics analysis indicated that RI was the most informative index with the optimum threshold of 0.775, which provided 82.8% sensitivity, 83.7% specificity, and 82.8% accuracy. Conclusions Semiquantitative analysis of 201 Tl SPECT provides useful information for the differentiation between tumor recurrence and radiation necrosis in metastatic brain tumors and high-grade gliomas after GKS, and the RI may be the most valuable index for this purpose.

We previously reported that μ-oxo N,N’-bis(salicylidene)ethylenediamine iron [Fe(Salen)], a magnetic organic compound, has direct anti-tumor activity, and generates heat in an alternating magnetic field (AMF). We showed that Fe(Salen) nanoparticles are useful for combined hyperthermia-chemotherapy of tongue cancer. Here, we have examined the effect of Fe(Salen) on human glioblastoma (GB). Fe(Salen) showed in vitro anti-tumor activity towards several human GB cell lines. It inhibited cell proliferation, and its apoptosis-inducing activity was greater than that of clinically used drugs. Fe(Salen) also showed in vivo anti-tumor activity in the mouse brain. We evaluated the drug distribution and systemic side effects of intracerebrally injected Fe(Salen) nanoparticles in rats. Further, to examine whether hyperthermia, which was induced by exposing Fe(Salen) nanoparticles to AMF, enhanced the intrinsic anti-tumor effect of Fe(Salen), we used a mouse model grafted with U251 cells on the left leg. Fe(Salen), BCNU, or normal saline was injected into the tumor in the presence or absence of AMF exposure. The combination of Fe(Salen) injection and AMF exposure showed a greater anti-tumor effect than did either Fe(Salen) or BCNU alone. Our results indicate that hyperthermia and chemotherapy with single-drug nanoparticles could be done for GB treatment.

A new solid composite of poly(N-vinylacetamide), lithium trifluoromethanesulfonate, and poly(ethylene glycol) was prepared and characterized as a polymer electrolyte with high conductivity.

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

Background: We previously reported the identification of a novel nano-organic compound, EI236, an anti-cancer agent with intrinsic magnetic property. In addition to anti-cancer effect, its ferromagnetic property contributes to unique features.1) It can be attracted by a magnet. 2) It can be visualized by magnetic resonance imaging (MRI). Hereby, we have identified the key mechanism that contributes to magnetism by X-ray crystallographic analysis, and succeeded in generating a novel paclitaxel with intrinsic magnetism; this is a single paclitaxel compound, and is not a paclitaxel encapsulated in micelle with magnetic particles. Our aim is to examine its effect on triple negative-breast cancer (TNBC) cells. Material and Method: The magnetization of the magnetized paclitaxel was measured with a superconducting quantum interference device (SQUID) (Quantum Design MPMS7 system). Breast cancer cells, MDA-MB-453 (TNBC) and MCF7 (Non-TNBC), were obtained from RIKEN Bioresource center. Cell proliferation assay was performed using a commercially available kit, XTT Cell Proliferation Assay Kit. Apoptotic cells were stained with Annexin V, allophycocyanin conjugate and 7-amino-actinomycin D, and measured by fluorescence activated cell sorting (FACS), to evaluate early and late apoptosis. Cell cycle analysis was performed using The Cycletest™ Plus DNA Reagent Kit and assessed using FACS. Results: Plots of magnetization versus magnetic field revealed that the magnetized paclitaxel exhibits magnetic property in SQUID. Magnetized paclitaxel was easily attracted by a commercial bar magnet. Magnetized paclitaxel exhibits greater anti-cancer effect than original paclitaxel in TNBC and Non-TNBC cells in a dose-dependent manner. Magnetized paclitaxel induced apoptosis and G2/M arrest in cell cycle analysis in a dose-dependent manner, suggesting that magnetized paclitaxel retained the original anti-cancer property. In MRI T2 -weighted imaging, signal intensity was changed in a concentration-dependent manner with magnetized paclitaxel, but not with commercial available paclitaxel. Conclusion: These results suggested that various conventional anti-cancer drugs might be similarly magnetized, leading to novel drug development in future cancer chemotherapy. Citation Format: Masanari Umemura, Ayako Makino, Itaru Sato, Xianfeng Feng, Kayoko Oda, Makoto Ohtake, Satoshi Izuka, Maki Iwai, Kosuke Matsuo, Haruki Eguchi, Yoshihiro Ishikawa. A novel treatment for triple-negative breast cancer using intrinsic magnetized paclitaxel. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5399. doi:10.1158/1538-7445.AM2014-5399

The copolymerization of propylene with 1-butene was carried out in presence of the catalytic system TiCl4/Mg[(CH2)5CH3]2 in heptane. A transparent copolymer with a random distribution (r1 · r2 = 1,0) was obtained. The catalyst shows a considerably high activity. The rate of monomer addition was found to be independent of the chemical structure of the growing polymer chain end, which is quite different for the copolymerization of ethylene with propylene.