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Imaging of Metastatic Cancer Cells in Sentinel Lymph Nodes using Affibody Probes and Possibility of a Theranostic Approach

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      Abstract

      The accurate detection of lymph node metastases is essential for treatment success in early-stage malignant cancer. Sentinel lymph node (SLN) biopsy is the most effective procedure for detecting small or micrometastases that are undetectable by conventional imaging modalities. To demonstrate a new approach for developing a more efficient SLN biopsy procedure, we reported a two-stage imaging method combining lymphoscintigraphy and near-infrared (NIR) fluorescence imaging to depict metastatic cancer cells in SLNs in vivo. Furthermore, the theranostic potential of the combined procedure was examined by cell culture and xenograft mouse model. Anti-HER2 and anti-epidermal growth factor receptor (EGFR) affibody probes were used for NIR fluorescence imaging. Strong NIR fluorescence signal intensity of the anti-EGFR affibody probe was observed in SAS cells (EGFR positive). Radioactivity in the SLNs was clearly observed in the in vivo studies. High anti-EGFR affibody NIR fluorescence intensity was observed in the metastatic lymph nodes in mice. The addition of the IR700-conjugated anti-EGFR affibody to the culture medium decreased the proliferation of SAS cells. Decreased proliferation was shown in Ki-67 immunohistochemistry in xenograft tumors. Our data suggest that a two-stage combined imaging method using lymphoscintigraphy and affibody probes may offer the direct visualization of metastatic lymph nodes as an easily applied technique in SLN biopsy. Although further animal studies are required to assess the effect of treating lymphatic metastasis in this approach, our study results provide a foundation for the further development of this promising imaging and treatment strategy for earlier lymph node metastasis detection and treatment.

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      Most cited references 46

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      Biomedical photoacoustic imaging.

       Paul Beard (2011)
      Photoacoustic (PA) imaging, also called optoacoustic imaging, is a new biomedical imaging modality based on the use of laser-generated ultrasound that has emerged over the last decade. It is a hybrid modality, combining the high-contrast and spectroscopic-based specificity of optical imaging with the high spatial resolution of ultrasound imaging. In essence, a PA image can be regarded as an ultrasound image in which the contrast depends not on the mechanical and elastic properties of the tissue, but its optical properties, specifically optical absorption. As a consequence, it offers greater specificity than conventional ultrasound imaging with the ability to detect haemoglobin, lipids, water and other light-absorbing chomophores, but with greater penetration depth than purely optical imaging modalities that rely on ballistic photons. As well as visualizing anatomical structures such as the microvasculature, it can also provide functional information in the form of blood oxygenation, blood flow and temperature. All of this can be achieved over a wide range of length scales from micrometres to centimetres with scalable spatial resolution. These attributes lend PA imaging to a wide variety of applications in clinical medicine, preclinical research and basic biology for studying cancer, cardiovascular disease, abnormalities of the microcirculation and other conditions. With the emergence of a variety of truly compelling in vivo images obtained by a number of groups around the world in the last 2-3 years, the technique has come of age and the promise of PA imaging is now beginning to be realized. Recent highlights include the demonstration of whole-body small-animal imaging, the first demonstrations of molecular imaging, the introduction of new microscopy modes and the first steps towards clinical breast imaging being taken as well as a myriad of in vivo preclinical imaging studies. In this article, the underlying physical principles of the technique, its practical implementation, and a range of clinical and preclinical applications are reviewed.
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        Arming antibodies: prospects and challenges for immunoconjugates.

        Immunoconjugates--monoclonal antibodies (mAbs) coupled to highly toxic agents, including radioisotopes and toxic drugs (ineffective when administered systemically alone)--are becoming a significant component of anticancer treatments. By combining the exquisite targeting specificity of mAbs with the enhanced tumor-killing power of toxic effector molecules, immunoconjugates permit sensitive discrimination between target and normal tissue, resulting in fewer toxic side effects than most conventional chemotherapeutic drugs. Two radioimmunoconjugates, ibritumomab tiuxetan (Zevalin) and tositumomab-131I (Bexxar), and one drug conjugate, gemtuzumab ozogamicin (Mylotarg), are now on the market. For the next generation of immunoconjugates, advances in protein engineering will permit greater control of mAb targeting, clearance and pharmacokinetics, resulting in significantly improved delivery to tumors of radioisotopes and potent anticancer drugs. Pre-targeting strategies, which separate the two functions of antibody-based localization and delivery or generation of the toxic agent into two steps, also promise to afford superior tumor targeting and therapeutic efficacy. Several challenges in optimizing immunoconjugates remain, however, including poor intratumoral mAb uptake, normal tissue conjugate exposure and issues surrounding drug potency and conditional release from mAb carriers. Nonetheless, highly promising results from preclinical models will continue to drive the clinical development of this therapeutic class.
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          Cancer Cell-Selective In Vivo Near Infrared Photoimmunotherapy Targeting Specific Membrane Molecules

          Three major modes of cancer therapies, surgery, radiation and chemotherapy, have been the mainstay of modern oncologic therapy. To minimize side effects, molecular targeted cancer therapies including armed antibody therapy have been developed with limited success. In this study, we developed a new type of molecular targeted cancer therapy, photoimmunotherapy (PIT), employing a target-specific photosensitizer based on a near infrared (NIR) phthalocyanine dye, IR700, conjugated to monoclonal antibodies (MAb) targeting epidermal growth factor receptors (EGFR). Cell death was induced immediately only upon irradiating, MAb-IR700 bound, target cells with NIR light. In vivo tumor shrinkage after irradiation with NIR light was observed only in target EGFR-expressing cells. The MAb-IR700 conjugates were most effective when bound to the cell membrane, producing no phototoxicity when not bound, suggesting a different mechanism for PIT compared with conventional photodynamic therapies. Target selective PIT enables treatment of cancer based on MAb binding on the cell membrane.
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            Author and article information

            Affiliations
            [1 ]Emeritus Professor, The Nippon Dental University, Tokyo, Japan, formerly of the Department of Oral and Maxillofacial Radiology, The Nippon Dental University School of Life Dentistry at Niigata, 1-8 Hamaura-cho, Chuo-ku, Niigata 951-8580, Japan
            [2 ]Department of Life Science Dentistry, The Nippon Dental University, 1-9-20 Fujimi, Chiyoda-ku, Tokyo 102-8159, Japan; harukay@ 123456ngt.ndu.ac.jp
            [3 ]Department of Oral and Maxillofacial Radiology, The Nippon Dental University School of Life Dentistry at Niigata, Niigata 951-8580, Japan; hayama@ 123456ngt.ndu.ac.jp
            [4 ]Basil Hetzel Institute for Translational Health Research, The Queen Elizabeth Hospital, 28 Woodville Road Woodville South, SA 5011, Australia
            [5 ]Department of Pathology, The Nippon Dental University School of Life Dentistry at Niigata, Niigata 951-8580, Japan; yokada@ 123456ngt.ndu.ac.jp
            [6 ]Division of Oral Bioengineering, Institute of Medicine and Dentistry, Niigata University, Division of Oral Bioengineering, Department of Tissue Regeneration and Reconstitution, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8541, Japan; kawase@ 123456dent.niigata-u.ac.jp
            [7 ]Department of Electrical and Electronic Engineering, Faculty of Engineering, Niigata University, Niigata 950-2181, Japan; takamasa@ 123456eng.niigata-u.ac.jp
            [8 ]Faculty of Engineering, Niigata University, Niigata 950-2181, Japan; ntsuboka@ 123456eng.niigata-u.ac.jp
            [9 ]Department of General Surgery, Tokyo Dental College Ichikawa General Hospital, Ichikawa, Chiba 272-8513, Japan; nowada@ 123456tdc.ac.jp
            [10 ]Division of Biomarker Discovery, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Chiba 277-8577, Japan; aochiai@ 123456east.ncc.go.jp
            [11 ]Laboratory of Cancer Biology, Department of Integrated Biosciences, Graduate School of Frontier Sciences, University of Tokyo, Kashiwa, Chiba 277-8561, Japan
            [12 ]Division of Pathology, Exploratory Oncology Research & Clinical Trial Center, National Cancer Center, Kashiwa, Chiba 277-8577, Japan; sfujii@ 123456east.ncc.go.jp
            [13 ]Division of Functional Imaging, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Chiba 277-8577, Japan; hifujii@ 123456east.ncc.go.jp
            Author notes
            [* ]Correspondence: tsuchimochi@ 123456ngt.ndu.ac.jp ; Tel.: +81-25-267-1500
            Journal
            Int J Mol Sci
            Int J Mol Sci
            ijms
            International Journal of Molecular Sciences
            MDPI
            1422-0067
            19 January 2019
            January 2019
            : 20
            : 2
            30669481 6359136 10.3390/ijms20020427 ijms-20-00427
            © 2019 by the authors.

            Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

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