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      Acridine Orange: A Review of Novel Applications for Surgical Cancer Imaging and Therapy


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          Introduction: Acridine orange (AO) was first extracted from coal tar in the late nineteenth century and was used as a fluorescent dye. In this paper, we review emergent research about novel applications of AO for fluorescence surgery and cancer therapy.

          Materials and methods: We performed a systematic search in the MEDLINE, PubMed, Cochrane library, Google Scholar, Embase, Web of Science, and Scopus database using combinations of the term “acridine orange” with the following: “surgical oncology,” “neuropathology,” “microsurgery,” “intraoperative fluorescence,” “confocal microscopy,” “pathology,” “endomicroscopy,” “guidance,” “fluorescence guidance,” “oncology,” “surgery,” “neurooncology,” and “photodynamic therapy.” Peer-reviewed articles published in English were included in this review. We have also scanned references for relevant articles.

          Results: We have reviewed studies on the various application of AO in microscopy, endomicroscopy, intraoperative fluorescence guidance, photodynamic therapy, sonodynamic therapy, radiodynamic therapy.

          Conclusion: Although the number of studies on the clinical use of AO is limited, pilot studies have demonstrated the safety and feasibility of its application as an intraoperative fluorescent dye and as a novel photo- and radio-sensitizator. Further clinical studies are necessary to more definitively assess the clinical benefit AO-based fluorescence guidance, therapy for sarcomas, and to establish feasibility of this new approach for the treatment of other tumor types.

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          Most cited references62

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          Treating cancer with sonodynamic therapy: A review

          Sonodynamic therapy (SDT) has emerged as a promising option for the minimally invasive treatment of solid cancerous tumours. SDT requires the combination of three distinct components: a sensitising drug, ultrasound, and molecular oxygen. Individually, these components are non-toxic but when combined together generate cytotoxic reactive oxygen species (ROS). The major advantage of SDT over its close relative photodynamic therapy (PDT), is the increased penetration of ultrasound through mammalian tissue compared to light. As a result, SDT can be used to treat a wider array of deeper and less accessible tumours than PDT. In this article, we critically review the current literature on SDT and discuss strategies that have been developed in combination with SDT to enhance the therapeutic outcome.
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            Nanoscale metal-organic frameworks for mitochondria-targeted radiotherapy-radiodynamic therapy

            Selective delivery of photosensitizers to mitochondria of cancer cells can enhance the efficacy of photodynamic therapy (PDT). Though cationic Ru-based photosensitizers accumulate in mitochondria, they require excitation with less penetrating short-wavelength photons, limiting their application in PDT. We recently discovered X-ray based cancer therapy by nanoscale metal–organic frameworks (nMOFs) via enhancing radiotherapy (RT) and enabling radiodynamic therapy (RDT). Herein we report Hf-DBB-Ru as a mitochondria-targeted nMOF for RT-RDT. Constructed from Ru-based photosensitizers, the cationic framework exhibits strong mitochondria-targeting property. Upon X-ray irradiation, Hf-DBB-Ru efficiently generates hydroxyl radicals from the Hf6 SBUs and singlet oxygen from the DBB-Ru photosensitizers to lead to RT-RDT effects. Mitochondria-targeted RT-RDT depolarizes the mitochondrial membrane to initiate apoptosis of cancer cells, leading to significant regression of colorectal tumors in mouse models. Our work establishes an effective strategy to selectively target mitochondria with cationic nMOFs for enhanced cancer therapy via RT-RDT with low doses of deeply penetrating X-rays.
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              A test for the practical evaluation of male fertility by acridine orange (AO) fluorescence.

              A new and practical test for evaluating the fertility of a male subject has been developed. Twenty-eight donors whose semen had induced at least one pregnancy resulting in a normal delivery and 61 patients attending our infertility clinic were studied. Semen smears stained with acridine orange were read on a fluorescence microscope; sperm heads appeared either green (fertile) or red ( nonfertile ). We introduce the concept of an "effective sperm count" which is obtained by multiplying the percentage of green-fluorescing sperm by the actual sperm count. Of our fertile subjects, 27 of 28 (96.4%) exhibited an effective sperm count of greater than or equal to 50 million/ml, while 60 of 61 (98.3%) infertile patients fell below this value. The percent green correlates with neither actual sperm count nor motility, indicating that this test measures a new parameter of male fertility.

                Author and article information

                Front Oncol
                Front Oncol
                Front. Oncol.
                Frontiers in Oncology
                Frontiers Media S.A.
                24 September 2019
                : 9
                : 925
                [1] 1Neurosurgery and Innovative Medicine Department, Irkutsk State Medical University , Irkutsk, Russia
                [2] 2Irkutsk Scientific Center of Surgery and Traumatology , Irkutsk, Russia
                [3] 3University of Arizona College of Medicine , Phoenix, AZ, United States
                [4] 4Federal State Autonomous Institution “N. N. Burdenko National Scientific and Practical Center for Neurosurgery” of the Ministry of Healthcare of the Russian Federation , Moscow, Russia
                Author notes

                Edited by: Jonathan T. C. Liu, University of Washington, United States

                Reviewed by: Laurence Gluch, The Strathfield Breast Centre, Australia; Guolin Ma, China-Japan Friendship Hospital, China; Joseph Georges, Philadelphia College of Osteopathic Medicine, United States

                *Correspondence: Vadim A. Byvaltsev byval75vadim@ 123456yandex.ru

                This article was submitted to Cancer Imaging and Image-directed Interventions, a section of the journal Frontiers in Oncology

                Copyright © 2019 Byvaltsev, Bardonova, Onaka, Polkin, Ochkal, Shepelev, Aliyev and Potapov.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                : 15 April 2019
                : 04 September 2019
                Page count
                Figures: 1, Tables: 0, Equations: 0, References: 63, Pages: 8, Words: 6238
                Mini Review

                Oncology & Radiotherapy
                acridine orange,radiodynamic therapy,photodynamic therapy,intraoperative fluorescence,surgical cancer imaging


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