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      Evaluation of methotrexate-conjugated gadolinium(III) for cancer diagnosis and treatment

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          Abstract

          Background

          Gliomas are one of the most common types of primary brain tumors. It is usually evaluated by gadolinium(III)-based contrast agents by magnetic resonance imaging (MRI) in the clinic. Methotrexate (MTX), as a type of folate analog that inhibits the enzyme dihydrofolate reductase, is widely used as a chemotherapeutic agent to treat gliomas in the experiment.

          Purpose

          In this study, a novel theranostic agent MTX-DOTA-Gd (MTX-Gd) was synthesized, which integrates magnetic resonance imaging (MRI) with anticancer treatment.

          Methods

          MTX-Gd was synthesized by connecting MTX and Gd through 1,4,7,10-tetraazacy-clododecane-1,4,7,10-tetraacetic acid (DOTA). The characterization of MTX-Gd was detected by ultraviolet (UV) and infrared spectroscopy (IR). To confirm the antitumor effect of MTX-Gd, the cytotoxicity of MTX-Gd was examined by the MTT assay. The contrast enhancement of the MTX-Gd was measured through MRI in vitro. Then, nude mice bearing C6 tumor xenografts were used to study in vivo imaging capabilities.

          Results

          The ultraviolet-visible-near infrared radiation (UV-NIR) absorption curve indicated that MTX-Gd had a broad absorption in the region of 500-700 nm. The formation of MTX-Gd was confirmed from the characteristic bands of MTX-DOTA-Gd in the 1413 cm −1 (C-N), 1577 cm −1 (−NH 2), and 3429 cm −1 (N-H), in the fourier-transform infrared (FTIR) spectra. MTX-Gd showed little difference in the cell viability compared with MTX, except for the highest concentration (270 μM). In vitro, the imaging of MTX-Gd was significantly brighter than Gd-DOTA at the same concentration, and the brightness and signal intensity of MRI were increased followed by the increased concentration of MTX-Gd. And it also showed that MTX was not visualized on MRI. The other images revealed that the concentration of 4 mM MTX-Gd had the same imaging effect with the concentration of 10 mM Gd-DOTA. Then, MTX-Gd was injected in nude mice bearing C6 tumor xenografts through the tail vein. Significant contrast enhancement was observed at the tumor site from 0.5 h to 3 h. The signal of tumor area was strongest at 3 h due to accumulation by size effect of macromolecules.

          Conclusion

          A novel stable and unique theranostic agent (MTX-Gd) was successfully synthe-sized, and it has good stability, strong anticancer ability and excellent magnetic capacity. The methotrexate component of MTX-Gd, as a chemotherapeutic agent, played an important role in targeted therapies of cancer. The DOTA-Gd component of MTX-Gd performed as the MRI contrast agent. The superior MRI imaging performance and synergetic chemical antineoplastic ability of MTX-Gd was revealed, and it has great potential in the diagnosis and treatment of glioma and potentially other cancers, with prospects of clinical application in the near future.

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          Most cited references 37

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          Theranostic nanomedicine.

          Nanomedicine formulations aim to improve the biodistribution and the target site accumulation of systemically administered (chemo)therapeutic agents. Many different types of nanomedicines have been evaluated over the years, including for instance liposomes, polymers, micelles and antibodies, and a significant amount of evidence has been obtained showing that these submicrometer-sized carrier materials are able to improve the balance between the efficacy and the toxicity of therapeutic interventions. Besides for therapeutic purposes, nanomedicine formulations have in recent years also been increasingly employed for imaging applications. Moreover, paralleled by advances in chemistry, biology, pharmacy, nanotechnology, medicine and imaging, several different systems have been developed in the last decade in which disease diagnosis and therapy are combined. These so-called (nano) theranostics contain both a drug and an imaging agent within a single formulation, and they can be used for various different purposes. In this Account, we summarize several exemplary efforts in this regard, and we show that theranostic nanomedicines are highly suitable systems for monitoring drug delivery, drug release and drug efficacy. The (pre)clinically most relevant applications of theranostic nanomedicines relate to their use for validating and optimizing the properties of drug delivery systems, and to their ability to be used for pre-screening patients and enabling personalized medicine. Regarding the former, the combination of diagnostic and therapeutic agents within a single formulation provides real-time feedback on the pharmacokinetics, the target site localization and the (off-target) healthy organ accumulation of nanomedicines. Various examples of this will be highlighted in this Account, illustrating that by non-invasively visualizing how well carrier materials are able to deliver pharmacologically active agents to the pathological site, and how well they are able to prevent them from accumulating in potentially endangered healthy tissues, important information can be obtained for optimizing the basic properties of drug delivery systems, as well as for improving the balance between the efficacy and the toxicity of targeted therapeutic interventions. Regarding personalized medicine, it can be reasoned that only in patients which show high levels of target site accumulation, and which respond well to the first couple of treatment cycles, targeted therapy should be continued, and that in those in which this is not the case, other therapeutic options should be considered. Based on these insights, we expect that ever more efforts will be invested in developing theranostic nanomedicines, and that these systems and strategies will contribute substantially to realizing the potential of personalized medicine.
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            Diagnosis and treatment of primary CNS lymphoma in immunocompetent patients: guidelines from the European Association for Neuro-Oncology.

            The management of primary CNS lymphoma is one of the most controversial topics in neuro-oncology because of the complexity of the disease and the very few controlled studies available. In 2013, the European Association of Neuro-Oncology created a multidisciplinary task force to establish evidence-based guidelines for immunocompetent adults with primary CNS lymphoma. In this Review, we present these guidelines, which provide consensus considerations and recommendations for diagnosis, assessment, staging, and treatment of primary CNS lymphoma. Specifically, we address aspects of care related to surgery, systemic and intrathecal chemotherapy, intensive chemotherapy with autologous stem-cell transplantation, radiotherapy, intraocular manifestations, and management of elderly patients. The guidelines should aid clinicians in their daily practice and decision making, and serve as a basis for future investigations in neuro-oncology.
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              High-relaxivity MRI contrast agents: where coordination chemistry meets medical imaging.

              The desire to improve and expand the scope of clinical magnetic resonance imaging (MRI) has prompted the search for contrast agents of higher efficiency. The development of better agents requires consideration of the fundamental coordination chemistry of the gadolinium(III) ion and the parameters that affect its efficacy as a proton relaxation agent. In optimizing each parameter, other practical issues, such as solubility and in vivo toxicity, must also be addressed, making the attainment of safe, high-relaxivity agents a challenging goal. This Minireview presents recent advances in the field, with an emphasis on gadolinium(III) hydroxypyridinone chelate complexes.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Drug Design, Development and Therapy
                Dove Medical Press
                1177-8881
                2018
                05 October 2018
                : 12
                : 3301-3309
                Affiliations
                [1 ]Department of Nuclear Medicine, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, PR China, vincentheyong@ 123456163.com
                [2 ]Department of Radiology, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, PR China, wubo5317@ 123456whu.edu.cn
                Author notes
                Correspondence: Yong He, Department of Nuclear Medicine, Zhongnan Hospital of Wuhan University, Wuhan University, 169 Donghu Road street, Wuhan 430071, Hubei province, PR China, Tel +86 27 6781 2698, Email vincentheyong@ 123456163.com
                Bo Wu, Department of Radiology, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, PR China, Tel +86 27 6781 2533, Email wubo5317@ 123456whu.edu.cn
                Article
                dddt-12-3301
                10.2147/DDDT.S178569
                6181113
                © 2018 Xu et al. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

                Categories
                Original Research

                Pharmacology & Pharmaceutical medicine

                theranostics, methotrexate, glioma, gadolinium

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