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      68Ga and 188Re Starch-Based Microparticles as Theranostic Tool for the Hepatocellular Carcinoma: Radiolabeling and Preliminary In Vivo Rat Studies

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          Abstract

          Purpose

          This work aims to develop, validate and optimize the radiolabeling of Starch-Based Microparticles (SBMP) by 188Re and 68Ga in the form of ready-to-use radiolabeling kits, the ultimate goal being to obtain a unique theranostic vector for the treatment of Hepatocellular Carcinoma.

          Methods

          Optimal labeling conditions and composition of freeze-dried kits were defined by monitoring the radiochemical purity while varying several parameters. In vitro stability studies were carried out, as well as an in vivo biodistribution as a preliminary approach with the intra-arterial injection of 68Ga radiolabeled SBMP into the hepatic artery of DENA-induced rats followed by PET/CT imaging.

          Results

          Kits were optimized for 188Re and 68Ga with high and stable radiochemical purity (>95% and >98% respectively). The in vivo preliminary study was successful with more than 95% of activity found in the liver and mostly in the tumorous part.

          Conclusion

          SBMP are a promising theranostic agent for the Selective Internal Radiation Therapy of Hepatocellular carcinoma.

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          Most cited references49

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            A molecular imaging primer: modalities, imaging agents, and applications.

            Molecular imaging is revolutionizing the way we study the inner workings of the human body, diagnose diseases, approach drug design, and assess therapies. The field as a whole is making possible the visualization of complex biochemical processes involved in normal physiology and disease states, in real time, in living cells, tissues, and intact subjects. In this review, we focus specifically on molecular imaging of intact living subjects. We provide a basic primer for those who are new to molecular imaging, and a resource for those involved in the field. We begin by describing classical molecular imaging techniques together with their key strengths and limitations, after which we introduce some of the latest emerging imaging modalities. We provide an overview of the main classes of molecular imaging agents (i.e., small molecules, peptides, aptamers, engineered proteins, and nanoparticles) and cite examples of how molecular imaging is being applied in oncology, neuroscience, cardiology, gene therapy, cell tracking, and theranostics (therapy combined with diagnostics). A step-by-step guide to answering biological and/or clinical questions using the tools of molecular imaging is also provided. We conclude by discussing the grand challenges of the field, its future directions, and enormous potential for further impacting how we approach research and medicine.
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              Hypoxia and anemia: factors in decreased sensitivity to radiation therapy and chemotherapy?

              Hypoxia is a common feature of solid tumors that occurs across a wide variety of malignancies. Hypoxia and anemia (which contributes to tumor hypoxia) can lead to ionizing radiation and chemotherapy resistance by depriving tumor cells of the oxygen essential for the cytotoxic activities of these agents. Hypoxia may also reduce tumor sensitivity to radiation therapy and chemotherapy through one or more indirect mechanisms that include proteomic and genomic changes. These effects, in turn, can lead to increased invasiveness and metastatic potential, loss of apoptosis, and chaotic angiogenesis, thereby further increasing treatment resistance. Investigations of the prognostic significance of pretreatment tumor oxygenation status have shown that hypoxia (oxygen tension [pO(2)] value < or =10 mmHg) is associated with lower overall and disease-free survival, greater recurrence, and less locoregional control in head and neck carcinoma, cervical carcinoma, and soft-tissue sarcoma. In view of the deleterious effect of hypoxia on standard cancer treatment, a variety of hypoxia- and anemia-targeted therapies have been studied in an effort to improve therapeutic effectiveness and patient outcomes. Early evidence from experimental and clinical studies suggests the administration of recombinant human erythropoietin (rHuEPO) may enhance the effectiveness of radiation therapy and chemotherapy by increasing hemoglobin levels and ameliorating anemia in patients with disease- or treatment-related anemia. However, further research is needed in the area of hypoxia-related treatment resistance and its reversal.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                14 October 2016
                2016
                : 11
                : 10
                : e0164626
                Affiliations
                [1 ]INSERM UMR-S 1066 MINT (Micro- et Nano-médecines Biomimétiques), University of Angers, Angers, France
                [2 ]Nuclear Medicine department, CHU de Liège, University of Liège, Liège, Belgium
                [3 ]Animal Facility, Experimental Surgery, GIGA-R & Credec, University of Liège, Liège, Belgium
                [4 ]Nuclear Medicine Department, Centre de Lutte Contre le Cancer (CLCC) Eugène Marquis, INSERM U991, Rennes, France
                [5 ]Nuclear Medicine department, CHU d'Angers, University of Angers, Angers, France
                [6 ]PRIMEX (Plateforme de Radiobiologie et d'IMagerie EXperimentale), University of Angers, Angers, France
                Helsingin Yliopisto, FINLAND
                Author notes

                Competing Interests: The authors have read the journal's policy and the authors of this manuscript have the following competing interests: F. Lacoeuille and F. Hindré are co-inventors of the patent WO2009013358 under the license of Laboratoires Cyclopharma. R. Hustinx is an advisor for Cyclopharma. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

                • Conceptualization: EV PD GM FH RH FL.

                • Formal analysis: EV FL.

                • Funding acquisition: EV OC FH RH FL.

                • Investigation: EV PD GM CB LD FL.

                • Methodology: EV PD GM CB LD FH RH FL.

                • Project administration: OC FH RH FL.

                • Resources: EV PD GM CB LD NL OC FH RH FL.

                • Supervision: OC FH RH FL.

                • Validation: EV FH RH FL.

                • Visualization: EV.

                • Writing – original draft: EV.

                • Writing – review & editing: EV FH RH FL.

                Author information
                http://orcid.org/0000-0002-6878-0686
                Article
                PONE-D-16-21809
                10.1371/journal.pone.0164626
                5065223
                27741267
                941c907b-963f-446b-a307-921f9749656c
                © 2016 Verger et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 31 May 2016
                : 28 September 2016
                Page count
                Figures: 3, Tables: 2, Pages: 17
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/501100001665, Agence Nationale de la Recherche;
                Award ID: n°ANR-11-LABX-0018-01
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/501100001665, Agence Nationale de la Recherche;
                Award ID: n°ANR-11-LABX-0018-01
                Award Recipient :
                Funded by: Ministère de l'Enseignement Supérieur et de la Recherche in the frame of NanoFar Erasmus Mundus Joint Doctorate program
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/501100001665, Agence Nationale de la Recherche;
                Award ID: n°ANR-11-LABX-0018-01
                Award Recipient :
                This work has been supported by a grant from the Ministère de l'Enseignement Supérieur et de la Recherche in the frame of the Erasmus Mundus Joint Doctorate NanoFar program (EV); and has been supported in part by a grant from the French National Agency for Research called "Investissements d'Avenir" Labex IRON n°ANR-11-LABX-0018-01 (FH, FL, OC). This work was authorized by Laboratoires Cyclopharma, through patent WO2009013358. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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