Heptamethine carbocyanine DZ-1 dye for near-infrared fluorescence imaging of hepatocellular carcinoma

Abstract

Near-infrared fluorescence (NIRF) dyes have recently emerged as promising tools for non-invasive imaging of different types of cancers. Here, we explored the potential utility of a NIRF DZ-1 dye, with dual imaging and tumour targeting functions, in hepatocellular carcinoma (HCC). We showed the preferential uptake of DZ-1 by HCC cells in vitro and in derived subcutaneous/orthotopic tumour xenografts, accompanied by a minimal effect on normal cells. DZ-1 simplified tumour growth profiling as well, since we were able to correlate NIRF signals with tumour volume and/or tumour-emitting luminescence in mice. Using both orthotopic tumour transplantation and cirrhosis models in parallel, we demonstrated the ability of DZ-1 to differentiate liver tumour from cirrhosis. DZ-1 showed superiority in HCC imaging over indocyanine green by demonstrating significantly enhanced tumour-targeting specificity. At the cellular level, DZ-1 was mainly retained in mitochondria and lysosomes. Additionally, DZ-1 fluorescence spectroscopy has been used for the intraoperative navigation of rabbit liver cancer, to determine surgical margins. We showed that tumor hypoxia and select organic anion-transporting polypeptide genes mediate NIRF dye uptake in HCC, which was supported by clinical evidence. All these findings represent the first evidence that DZ-1 is an effective molecular probe for tumour-specific imaging in HCC, and provide insights into the development of a new generation of imaging agents for intraoperative guidance of cancer surgery.

Targeting Burkitt lymphoma with a tumor cell–specific heptamethine carbocyanine‐cisplatin conjugate

“…D). DZ‐CIS NIR signals were detected at least 7 days after a single administration, like our prototype IR783 and MHI‐148 analogs . DZ‐CIS is prevented from diffusing out from cancer cells by interaction with cellular nucleic acids and proteins …”

“…DZ is tumor cell-specific, efficiently accumulating in xenograft tumors 24 hours after administration. [31][32][33] The synthesis of DZ-CIS conjugate used a succinic ester linker (Fig. 1).…”

“…DZ exhibits tumor cell specificity, accumulates preferentially in tumors in vivo and clears efficiently from normal tissues and organs. 18,31 DZ-CIS has similar tumor cell targeting specificity and killed Burkitt Cancer July 1, 2019 lymphoma cells preferentially. Mesenchymal stromal cells tagged with GFP survived treatment (Fig.…”

NIRF Optical/PET Dual-Modal Imaging of Hepatocellular Carcinoma Using Heptamethine Carbocyanine Dye

“…DAPI was purchased from Tiangen (Shanghai, China). Hep3B-3.1 transfected with luciferase cells (Hep3B-3.1-Luc) were derived previously by our lab [ 22 , 24 ] and cultured in modified Eagle's medium (MEM) supplemented with 10% fetal bovine serum and 1% penicillin/streptomycin (Thermo Scientific, Waltham, MA, USA). Rabbit VX-2 liver tumor tissue was preserved by our lab.…”

“…Although a suite of methods has been developed for early detection with early therapeutic intervention, diagnosing HCC early in clinical management is difficult because signs and symptoms often do not appear until the later stages, leading to a poor survival rate for most HCC cases [ 20 , 21 ]. Additionally, most agents are eventually deposited in the liver to some extent for metabolism after entering and circulating in the body, where they then release signals, obstructing the precise differentiation of HCC from normal/benign liver tissues; this inhibits a firm diagnosis, particularly at early disease stages [ 22 ]. HCC tumor heterogeneity further complicates the results of molecular probes that only target a single antigen or metabolic substrate for tumor visualization.…”