Targeting tumor hypoxia with 2-nitroimidazole-indocyanine green dye conjugates

Abstract

Abstract. Tumor hypoxia is a major indicator of treatment resistance to chemotherapeutic drugs, and fluorescence optical tomography has tremendous potential to provide clinically useful, functional information by identifying tumor hypoxia. The synthesis of a 2-nitroimidazole-indocyanine green conjugate using a piperazine linker (piperazine-2-nitroimidazole-ICG) capable of robust fluorescent imaging of tumor hypoxia is described. In vivo mouse tumor imaging studies were completed and demonstrate an improved imaging capability of the new dye relative to an earlier version of the dye that was synthesized with an ethanolamine linker (ethanolamine-2-nitroimidazole-ICG). Mouse tumors located at imaging depths of 1.5 and 2.0 cm in a turbid medium were imaged at various time points after intravenous injection of the dyes. On average, the reconstructed maximum fluorescence concentration of the tumors injected with piperazine-2-nitroimidazole-ICG was twofold higher than that injected with ethanolamine-2-nitroimidazole-ICG within 3 h postinjection period and 1.6 to 1.7 times higher beyond 3 h postinjection. The untargeted bis-carboxylic acid ICG completely washed out after 3 h postinjection. Thus, the optimal window to assess tumor hypoxia is beyond 3 h postinjection. These findings were supported with fluorescence images of histological sections of tumor samples and an immunohistochemistry technique for identifying tumor hypoxia.

Where do dyes go inside living cells? Predicting uptake, intracellular localisation, and accumulation using QSAR models

“…Moreover, such structural insights would apply to all dyes, not merely to those whose targeting was entirely dependent on the permeability/retention effect. In this context, note that three labelled-peptide smart probes that have recently been described [95] are all hydrophilic and all fall into the tumour-labelling zone of Figure 10, as do the lipophilic, but also amphiphilic, tumour-anoxia imaging probes described by Xu et al [96].…”

In vivo photoacoustic tumor tomography using a quinoline-annulated porphyrin as NIR molecular contrast agent

“…32 Briefly, 4T1 Luc cells were cultured at 37 °C with 5% CO 2 in a T75 flask (BD Biosciences, Bedford, MA); DMEM (Dulbecco’s Modified Eagle’s medium, Gibco, USA) medium supplemented with 10% FBS and 50 U/mL penicillin/streptomycin. After 3 passes, the cells were suspended in the DMEM and 1 × 10 5 cells were injected subcutaneously on top of the right leg of female BALB/c mice (6–8 weeks old, body weight ~20 g).…”

The Structure and Activity of Double-Nitroimidazoles. A Mini-Review

“…Another interesting approach to the synthesis and evaluation of bis-nitroimidazoles has been presented by Xu et al [15], in which the authors described the method for obtaining a more expanded structure of novel nitroimidazole indocyanine dye conjugate (2-nitroimidazole-ICG) (16) (Figure 8) using a piperazine linker for tumor-targeted hypoxia fluorescence tomography [15]. The activity of the new compound (16) was compared with that of the earlier known analogue of ethanolamine-2-nitroimidazole-ICG.…”