Innovative treatment for hepatocellular carcinoma (HCC)

Abstract

Indocyanine green (ICG) is not new in the field of liver surgery. Early studies performed in the 1980s and 1990s revealed the value of the ICG clearance test in predicting post-hepatectomy morbidity and mortality. ICG clearance and retention tests are crucial for determining precise liver function before liver surgery and offer several benefits for safe surgery. Whereas ICG is well-known and has long history in medicine, recent progress in infrared light technology over the last decade has highlighted another feature of ICG. For example, ICG fluorescence-guided surgery may change the next generation of liver surgery. In the near future, ICG with near-infrared (NIR) light photodynamic therapy (PDT) is expected to become a new treatment method for hepatocellular carcinoma (HCC). Furthermore, several aspects of the mechanisms of ICG accumulation in HCC cells have been revealed by important basic research studies. New imaging technologies and mechanistic findings keep ICG in the spotlight. In this article, we review three recently described topics of ICG which may contribute to the development of innovative and new treatments method for HCC, fluorescence-guided surgery, mechanism of ICG accumulation in HCC cells, PDT for HCC.

Keywords: Indocyanine green (ICG); accumulation mechanism; fluorescence-guided surgery; near-infrared light (NIR light); photodynamic therapy (PDT).

Figure 1

Identification of liver segment boundaries by injecting indocyanine green into the inferior branch of the portal vein for Couinaud’s segment IV. (A) Without fluorescence imaging; (B) under fluorescence imaging.

Figure 2

Identification of hepatocellular carcinoma using indocyanine green fluorescence imaging (PINPOINT, Stryker Japan K.K., Tokyo, Japan).

Figure 3

The suggested mechanism of hepatic metabolism of ICG. Hepatic uptake of ICG is facilitated by OATP1B3 and NTCP. During the intracellular transportation of ICG, it binds to the GST isozyme, forming phospholipid vesicles and bile salt/lipid hybrid micelles. Biliary excretion is facilitated by MDR3 and MRP2. ICG, indocyanine green; NTCP, Na⁺-taurocholate co-transporting polypeptide; GST, glutathione S-transferase.

Figure 4

HuH-7 xenograft tumors were observed in the center of abdomen of the transplanted mice (A). Twenty-four hours after ICG administration, HuH-7 xenograft tumors in mice exhibited uniform fluorescence under the fluorescence imaging system (B). ICG, indocyanine green.

Figure 5

Under fluorescence microscopy, normal tissue surrounding HuH-7 xenograft tumors produced no fluorescence. All HuH-7 cells, however, were fluorescent. Fluorescence was observed in the cytoplasm of HuH-7 cells, but not in the nucleus.

Figure 6

Temperature calibration analysis (lower panel, center of crossshaped sign) using thermography during ICG-NIR PDT. The temperature was 41.1 °C within 60 s after starting ICG-NIR PDT. ICG, indocyanine green; NIR, near-infrared; PDT, photodynamic therapy.

Figure 7

Large HuH-7 xenograft tumor observed in the mouse abdomen (A, triangular arrow). Later, a thin and obscure tumor was observed in the abdomen of the transplanted mice after ICG-NIR PDT (B, triangular arrow). ICG, indocyanine green; NIR, near-infrared; PDT, photodynamic therapy.