Near-infrared imaging holds promise for in-vivo cancer detection because of flow tissue autofluorescence and high tissue penetration depth. Cyanine dyes have shown much potential as non-targeting contrast agents for optical imaging; in particular, indocyanine green has long been implemented in clinical use. To improve targeting selectivity and delivery efficiency, common strategies with activatable technology need the chemical conjugation of suitable near-infrared emission range agents with tumour-specific ligands such as antibodies.1 Although these conjugated agents with tumour-specific antibodies or other ligands have shown promising efficacy in preclinical and clinical trials compared with conventional chemotherapy drugs, limitations in their delivery and specificity remain. For example, in-vivo studies have shown that only one to ten parts per 100 000 of intravenously administered monoclonal antibodies, of therapeutic or imaging agents, can reach their parenchymal targets, and only to specific tumour types.2 Furthermore, the chemical conjugation might affect the specificity, affinity, and distribution of the agents in cells and tissues.
Cyanine dyes in optical imaging of tumours
To overcome these limitations, a rational strategy is to develop near-infrared dyes with native tumour targeting properties. With this hypothesis, our research has identified a group of heptamethine cyanine dyes with improved near-infrared fluorescence emission profiles and active tumour targeting properties that do not require chemical conjugation. These cyanine dyes are lipophilic cations at 780 nm, and preferentially accumulate in the mitochondria of viable tumour cells because of their higher mitochondrial membrane potential, compared with normal cells, to reach a significant signal contrast for in-vivo tumour imaging.3, 4 The accumulation of these cyanine dyes is via an energy-dependent pathway (only by viable tumour cells), and can be distinguished from dead or apoptotic cells.
These cyanine dyes have superior optical properties for tumour imaging owing to a rigid cyclohexenyl ring in the heptamethine chain with a central chlorine atom that maintains photostability, increases quantum yield, and decreases photobleaching. The dyes have superb biocompatible, pharmacokinetic, and retention properties. They can persist in tumours over 2 weeks for repeated imaging, but free dyes in circulation can be excreted rapidly from the interstitial fluid, resulting in no apparent acute toxic effect and improved signal contrast of tumours. The cyanine dyes can reach a contrast index value up to 20, whereas previously, a contrast index in a tumour of more than 2·5 times compared with that in its surrounding tissue was regarded as substantial accumulation.5 Additionally, the fluorescence of these dyes was stable after formalin fixation, which raised the possibility of developing new and sensitive means of detecting tumours in harvested surgical specimens.6
Most human tumours have been identified with higher mitochondrial membrane potentials than normal cells, making these dyes attractive imaging agents for cancer detection.7 Therefore, cyanine dyes can be used non-invasively to detect tumour and tumour metastases in vivo, cancer cells in pathological specimens, and circulating cancer cells in blood to improve cancer detection, prognosis, and treatment.
CS initially made the concept and identified these heptamethine cyanine dyes with native tumour targeting and near-infrared imaging properties. CS is also an inventor on the pending patents for these cyanine dyes as tumour imaging agents. CZ, YS, and TC declared no conflicts of interest.
source: Lancet oncology
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