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

Abstract

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.

Keywords: acridine orange; intraoperative fluorescence; photodynamic therapy; radiodynamic therapy; surgical cancer imaging.

Figure 1

(A) Cytotoxic effect of acridine orange (AO)-charged exosomes derived from macrophages (Exo Mϕ-AO) compared to free AO against melanoma cell monolayer by cytofluorimetry assessment. Columns, mean percentages of cell death of two independent experiments run in triplicate; bars indicate standard deviation. p < 0.05. Figure adapted with permission from: Iessi et al. (43) (CC BY 4.0). (B) Fluorescence microscopy showing the formation of membrane “blebs” in melanoma cells treated with Exo Mϕ-AO (1 lg/ml) after 5 min of exposition to blue light. Figure adapted with permission from: Iessi et al. (43) (CC BY 4.0). (C) Upper image—Confocal laser endomicroscopy image of an animal glioblastoma stained with AO. Lower image—corresponding histology image. Image courtesy of Dr. Mark C. Preul. (D) Macroscopic fluorescence view of mouse osteosarcoma subcutaneously inoculated in the back of nude mouse after blue light excitation at 2 h after AO injection through the tail vein. Tumors emit green fluorescence (arrows). Injection site of the tail vein also emits green fluorescence Figure adapted with permission from: Kusuzaki et al. (6) (CC-BY 3.0).