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      Efficient treatment of breast cancer xenografts with multifunctionalized iron oxide nanoparticles combining magnetic hyperthermia and anti-cancer drug delivery

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          Abstract

          Introduction

          Tumor cells can effectively be killed by heat, e.g. by using magnetic hyperthermia. The main challenge in the field, however, is the generation of therapeutic temperatures selectively in the whole tumor region. We aimed to improve magnetic hyperthermia of breast cancer by using innovative nanoparticles which display a high heating potential and are functionalized with a cell internalization and a chemotherapeutic agent to increase cell death.

          Methods

          The superparamagnetic iron oxide nanoparticles (MF66) were electrostatically functionalized with either Nucant multivalent pseudopeptide (N6L; MF66-N6L), doxorubicin (DOX; MF66-DOX) or both (MF66-N6LDOX). Their cytotoxic potential was assessed in a breast adenocarcinoma cell line MDA-MB-231. Therapeutic efficacy was analyzed on subcutaneous MDA-MB-231 tumor bearing female athymic nude mice.

          Results

          All nanoparticle variants showed an excellent heating potential around 500 W/g Fe in the alternating magnetic field (AMF, conditions: H = 15.4 kA/m, f = 435 kHz). We could show a gradual inter- and intracellular release of the ligands, and nanoparticle uptake in cells was increased by the N6L functionalization. MF66-DOX and MF66-N6LDOX in combination with hyperthermia were more cytotoxic to breast cancer cells than the respective free ligands. We observed a substantial tumor growth inhibition (to 40% of the initial tumor volume, complete tumor regression in many cases) after intratumoral injection of the nanoparticles in vivo. The proliferative activity of the remaining tumor tissue was distinctly reduced.

          Conclusion

          The therapeutic effects of breast cancer magnetic hyperthermia could be strongly enhanced by the combination of MF66 functionalized with N6L and DOX and magnetic hyperthermia. Our approach combines two ways of tumor cell killing (magnetic hyperthermia and chemotherapy) and represents a straightforward strategy for translation into the clinical practice when injecting nanoparticles intratumorally.

          Electronic supplementary material

          The online version of this article (doi:10.1186/s13058-015-0576-1) contains supplementary material, which is available to authorized users.

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          Most cited references 38

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          Thermal dose determination in cancer therapy.

          With the rapid development of clinical hyperthermia for the treatment of cancer either alone or in conjunction with other modalities, a means of measuring a thermal dose in terms which are clinically relevant to the biological effect is needed. A comparison of published data empirically suggests a basic relationship that may be used to calculate a "thermal dose." From a knowledge of the temperature during treatment as a function of time combined with a mathematical description of the time-temperature relationship, an estimate of the actual treatment calculated as an exposure time at some reference temperature can be determined. This could be of great benefit in providing a real-time accumulated dose during actual patient treatment. For the purpose of this study, a reference temperature of 43 degrees C has been arbitrarily chosen to convert all thermal exposures to "equivalent-minutes" at this temperature. This dose calculation can be compared to an integrated calculation of the "degree-minutes" to determine its prognostic ability. The time-temperature relationship upon which this equivalent dose calculation is based does not predict, nor does it require, that different tissues have the same sensitivity to heat. A computer program written in FORTRAN is included for performing calculations of both equivalent-minutes (t43) and degree-minutes (tdm43). Means are provided to alter the reference temperature, the Arrhenius "break" temperature and the time-temperature relationship both above and below the "break" temperature. In addition, the effect of factors such as step-down heating, thermotolerance, and physiological conditions on thermal dose calculations are discussed. The equations and methods described in this report are not intended to represent the only approach for thermal dose estimation; instead, they are intended to provide a simple but effective means for such calculations for clinical use and to stimulate efforts to evaluate data in terms of therapeutically useful thermal units.
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            Theranostic magnetic nanoparticles.

            Early detection and treatment of disease is the most important component of a favorable prognosis. Biomedical researchers have thus invested tremendous effort in improving imaging techniques and treatment methods. Over the past decade, concepts and tools derived from nanotechnology have been applied to overcome the problems of conventional techniques for advanced diagnosis and therapy. In particular, advances in nanoparticle technology have created new paradigms for theranostics, which is defined as the combination of therapeutic and diagnostic agents within a single platform. In this Account, we examine the potential advantages and opportunities afforded by magnetic nanoparticles as platform materials for theranostics. We begin with a brief overview of relevant magnetic parameters, such as saturation magnetization, coercivity, and magnetocrystalline anisotropy. Understanding the interplay of these parameters is critical for optimizing magnetic characteristics needed for effective imaging and therapeutics, which include magnetic resonance imaging (MRI) relaxivity, heat emission, and attractive forces. We then discuss approaches to constructing an MRI nanoparticle contrast agent with high sensitivity. We further introduce a new design concept for a fault-free contrast agent, which is a T1 and T2 dual mode hybrid. Important capabilities of magnetic nanoparticles are the external controllability of magnetic heat generation and magnetic attractive forces for the transportation and movement of biological objects. We show that these functions can be utilized not only for therapeutic hyperthermia of cancer but also for controlled release of cancer drugs through the application of an external magnetic field. Additionally, the use of magnetic nanoparticles to drive mechanical forces is demonstrated to be useful for molecular-level cell signaling and for controlling the ultimate fate of the cell. Finally, we show that targeted imaging and therapy are made possible by attaching a variety of imaging and therapeutic components. These added components include therapeutic genes (small interfering RNA, or siRNA), cancer-specific ligands, and optical reporting dyes. The wide range of accessible features of magnetic nanoparticles underscores their potential as the most promising platform material available for theranostics.
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              Aptamer-functionalized PEG-PLGA nanoparticles for enhanced anti-glioma drug delivery.

              Targeted delivery of therapeutic nanoparticles in a disease-specific manner represents a potentially powerful technology especially when treating infiltrative brain tumors such as gliomas. We developed a nanoparticulate drug delivery system decorated with AS1411 (Ap), a DNA aptamer specifically binding to nucleolin which was highly expressed in the plasma membrane of both cancer cells and endothelial cells in angiogenic blood vessels, as the targeting ligand to facilitate anti-glioma delivery of paclitaxel (PTX). Ap was conjugated to the surface of PEG-PLGA nanoparticles (NP) via an EDC/NHS technique. With the conjugation confirmed by Urea PAGE and XPS, the resulting Ap-PTX-NP was uniformly round with particle size at 156.0 ± 54.8 nm and zeta potential at -32.93 ± 3.1 mV. Ap-nucleolin interaction significantly enhanced cellular association of nanoparticles in C6 glioma cells, and increased the cytotoxicity of its payload. Prolonged circulation and enhanced PTX accumulation at the tumor site was achieved for Ap-PTX-NP, which eventually obtained significantly higher tumor inhibition on mice bearing C6 glioma xenografts and prolonged animal survival on rats bearing intracranial C6 gliomas when compared with PTX-NP and Taxol(®). The results of this contribution demonstrated the potential utility of AS1411-functionalized nanoparticles for a therapeutic application in the treatment of gliomas. Copyright © 2011 Elsevier Ltd. All rights reserved.
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                Author and article information

                Contributors
                susanne.kossatz@outlook.de
                julia.grandke@med.uni-jena.de
                pierre.couleaud@imdea.org
                alfonso.latorre@imdea.org
                antonio.aires@imdea.org
                crosbiek@tcd.ie
                robert.ludwig@med.uni-jena.de
                heidi.daehring@med.uni-jena.de
                v_ettelt@web.de
                ana.lazaro@uam.es
                macarena.calero@uam.es
                sader.maha@gmail.com
                courty@u-pec.fr
                YVOLKOV@tcd.ie
                PRINAMEA@tcd.ie
                angeles.villanueva@uam.es
                alvaro.somoza@imdea.org
                aitziber.lopezcortajarena@imdea.org
                rodolfo.miranda@imdea.org
                ingrid.hilger@med.uni-jena.de
                Journal
                Breast Cancer Res
                Breast Cancer Research : BCR
                BioMed Central (London )
                1465-5411
                1465-542X
                13 May 2015
                13 May 2015
                2015
                : 17
                : 1
                Affiliations
                [ ]Institute for Diagnostic and Interventional Radiology, Jena University Hospital – Friedrich Schiller University Jena, D-07740 Jena, Germany
                [ ]Instituto Madrileño de Estudios Avanzados en Nanociencia (IMDEA Nanociencia), Campus Universitario de Cantoblanco, 28049 Madrid, Spain
                [ ]Unidad Asociada de Nanobiotecnología CNB-CSIC & IMDEA Nanociencia, Campus Universitario de Cantoblanco, 28049 Madrid, Spain
                [ ]School of Medicine, Trinity College Dublin, Dublin, Ireland
                [ ]Departamento de Biología, Universidad Autónoma de Madrid, Cantoblanco, 28049 Madrid, Spain
                [ ]Laboratoire CRRET, Université Paris EST Créteil, 61 Avenue du Général de Gaulle, 94010 Créteil, France
                [ ]CRANN, Trinity College, Dublin, Ireland
                Article
                576
                10.1186/s13058-015-0576-1
                4451751
                25968050
                © Kossatz et al.; licensee BioMed Central. 2015

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

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                Research Article
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                © The Author(s) 2015

                Oncology & Radiotherapy

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