Chonnam Med J.  2017 May;53(2):83-94. 10.4068/cmj.2017.53.2.83.

NIRF Heptamethine Cyanine Dye Nanocomplexes for Multi Modal Theranosis of Tumors

• Thomas RG
• Jeong YY

• KMID: 2379280
• DOI: http://doi.org/10.4068/cmj.2017.53.2.83

Abstract

Heptamethine cyanine dyes are categorized as a class of near infrared fluorescent (NIRF) dyes which have been discovered to have tumor targeting and accumulation capability. This unique feature of NIRF dye makes it a promising candidate for imaging, targeted therapy and also as a drug delivery vehicle for various types of cancers. The favored uptake of dyes only in cancer cells is facilitated by several factors which include organic anion-transporting polypeptides, high mitochondrial membrane potential and tumor hypoxia in cancer cells. Currently nanotechnology has opened possibilities for multimodal or multifunctional strategies for cancer treatment. Including heptamethine cyanine dyes in nanoparticle based delivery systems have generally improved its theranostic ability by several fold owing to the multiple functionalities and structural features of heptamethine dyes. For this reason, nanocomplexes with NIRF heptamethine cyanine dye probe are preferred over non-targeting dyes such as indo cyanine green (ICG). This review sums up current trends and progress in NIRF heptamethine cyanine dye, including dye properties, multifunctional imaging and therapeutic applications in cancer.

Keyword

Neoplasms; Fluorescent Dyes; Drug Delivery Systems; Nanotechnology

MeSH Terms

Anoxia
Coloring Agents
Drug Delivery Systems
Fluorescent Dyes
Membrane Potential, Mitochondrial
Nanoparticles
Nanotechnology
Peptides
Theranostic Nanomedicine
Coloring Agents
Fluorescent Dyes
Peptides

Figure

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  FIG. 1 Schema showing several applications of heptamethine cyanine dyes.

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  FIG. 2 Different NIRF heptamethine dye structures. Figure reproduced with permission from (25) and (26). Copyright © 2017 Impact Journals and MDPI AG.

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  FIG. 3 Preferential uptake and retention of MHI-148. (A) MHI-148 chemical structure. (B) Ex vivo NIR fluorescence imaging showed increased MHI-148 dye uptake by different types of canine spontaneous tumors (blue arrows) as compared to adjacent normal tissues (white arrows). (C) Preferential uptake of NIRF dye in gastric cancer tissues relative to that in gastric tissues. In vivo NIRF imaging of mice bearing either orthotopic luc-tagged gastric tumor xenografts (left) or gastric ulcers (right). (D) NIRF imaging of clinical gastric cancer tissues. Schematic outlining the experimental procedures for NIRF imaging of freshly resected clinical gastric tumor tissues (left). Gross morphology and NIRF imaging of representative tumor tissues surgically resected from one of three gastric cancer patients. Representative images are presented in all panels. Original magnification: 4×; scale bars represent 4 mm. Figure images and the accompanying legend are reproduced with permission from (2530). Copyright © 2017 Impact Journals.

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  FIG. 4 IR780-liposome and IR780-phospholipid micelle developed for NIRF optical imaging. (A) Structure of IR780 iodide free dye, an IR780-liposome, and IR780-phospholipid micelle. (B) Real-time NIRF imaging of IR780-phospholipid micelles using the glioma spontaneous mouse model. Bioluminescence imaging (BLI) indicates the location and status of the U87MG ectopic tumor. Figure images and accompanying legend are reproduced with permission from (35). Copyright © 2017 American Chemical Society.

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  FIG. 5 Synthesis, in vivo MRI, and photothermal therapy of (A) Mn-IR825@PDA-PEG and (B) IR825@PAH-IONP-PEG. Figure images and accompanying legend are reproduced with permission from (3741). Copyright © 2012 American Chemical Society and John Wiley & Sons, Inc.

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  FIG. 6 Photothermal therapy of cancer cells (A) Laser-induced thermal damage to cancer cells after accumulation of NIRF probes. (B) Synthesis of IR780 loaded PMDPC-IR780 micelle nanoparticles and its application in photothermal therapy. Figure images and accompanying legend are reproduced with permission from (4953). Copyright © 2017 Dove Press Ltd and American Chemical Society.

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  FIG. 7 Photodynamic therapy by light-induced ROS release and damage to cancer cells after NIRF probe accumulation. Figure images and accompanying legend are reproduced with permission from (53). Copyright © 2017 Dove Press Ltd.

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  FIG. 8 Sonodynamic therapy using IR780 (A) Schema showing the action of IR780 in releasing ROS using a sonodynamic transducer. Upon receiving US, IR780 that had accumulated in the tumor cells would receive US energy. When in the excited-state, IR780 restored back to the ground-state and releasing energy; 1O2 and H2O absorb the released energy and changed into 1O2 and H2O2. The superfluous 1O2 and H2O2 would subsequently cause the apoptosis and necrosis of tumor cells. (B) Quantification of ROS release by the DCF-DA assay in 4T1 cancer cells for 1O2 (a), H2O2 (b), and ·OH (c). (C) Cell viability analysis of 4T1 breast cancer cells incubated with PBS, 4µM, 10µM, or 16µM of IR780. 4T1 breast cancer cells were incubated with PBS or IR780 and then administered with US for 0 s, 20 s, or 40 s. Twenty-four hours later, the levels of 1O2 were evaluated. (D) Photograph of 4T1 tumors removed from mice 30 days after the tumor-bearing mice were treated by SDT with IR780. Figure images and accompanying legend are reproduced from (60). Copyright © 2017 Macmillan Publishers Limited.

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  FIG. 9 DITSL nanoparticles for PTT/Chemotherapy. (A) Schematic diagram of DOX release from DITSL under NIR-laser irradiation. The liposome membrane temperature would increase when the NIR-laser irradiation was applied. Destruction of the liposome membrane occurs when the membrane temperature reaches 42℃. (B) Schematic diagram of DITSL preparation. (C) The representative infrared photothermal images of tumors following laser irradiation. Figure images and accompanying legend are reproduced from (63). Copyright © 2017 Ivyspring International Publisher.

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  FIG. 10 Schematic of Tf-IR780 nanoparticle preparation, in vitro phototherapy, and biodistribution mediated by Tf-IR780 NPs. (A) Transferrin self-assembly with IR-780 with the help of dithiothreitol (DTT) to form Tf-IR780 NPs (B) Fluorescence images of CT-26 cells expressing singlet oxygen indicated by H2DCFDA staining for detection under photoirradiation (1 W/cm2; 808 nm) for 5 min (Scale bar=20µm). (C) In vivo fluorescence imaging in mice bearing CT-26 tumors administered with Tf-IR780 NPs (0.3 mg/kg, IR780). Figure images and accompanying legend are reproduced from (68). Copyright © 2017 Macmillan Publishers Limited.

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