The Application of Heptamethine Cyanine Dye DZ-1 and Indocyanine Green for Imaging and Targeting in Xenograft Models of Hepatocellular Carcinoma

Int J Mol Sci. 2017 Jun 21;18(6):1332. doi: 10.3390/ijms18061332.

Abstract

Near infrared fluorescence (NIRF) imaging has strong potential for widespread use in noninvasive tumor imaging. Indocyanine green (ICG) is the only Food and Drug Administration (FDA) -approved NIRF dye for clinical diagnosis; however, it is unstable and poorly targets tumors. DZ-1 is a novel heptamethine cyanine NIRF dye, suitable for imaging and tumor targeting. Here, we compared the fluorescence intensity and metabolism of DZ-1 and ICG. Additionally, we assayed their specificities and abilities to target tumor cells, using cultured hepatocellular carcinoma (HCC) cell lines, a nude mouse subcutaneous xenograft model of liver cancer, and a rabbit orthotopic transplantation model. We found that DZ-1 accumulates in tumor tissue and specifically recognizes HCC in subcutaneous and orthotopic models. The NIRF intensity of DZ-1 was one order of magnitude stronger than that of ICG, and DZ-1 showed excellent intraoperative tumor targeting in the rabbit model. Importantly, ICG accumulated at tumor sites, as well as in the liver and kidney. Furthermore, DZ-1 analog-gemcitabine conjugate (NIRG) exhibited similar tumor-specific targeting and imaging properties, including inhibition of tumor growth, in HCC patient-derived xenograft (PDX) mice. DZ-1 and NIRG demonstrated superior tumor-targeting specificity, compared to ICG. We show that DZ-1 is an effective molecular probe for specific imaging, targeting, and therapy in HCC.

Keywords: hepatocellular carcinoma; heptamethine cyanine dyes; intraoperative navigation; near-infrared fluorescence; optical imaging; xenograft model.

MeSH terms

  • Animals
  • Carbocyanines / analysis*
  • Carbocyanines / metabolism
  • Carcinoma, Hepatocellular / diagnostic imaging*
  • Carcinoma, Hepatocellular / metabolism
  • Cell Line, Tumor
  • Coloring Agents / analysis*
  • Coloring Agents / metabolism
  • Humans
  • Indocyanine Green / analysis*
  • Indocyanine Green / metabolism
  • Liver / diagnostic imaging*
  • Liver / metabolism
  • Liver Neoplasms / diagnostic imaging*
  • Liver Neoplasms / metabolism
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Optical Imaging / methods*
  • Rabbits

Substances

  • Carbocyanines
  • Coloring Agents
  • Indocyanine Green