Abstract
Quantification of tumor necrosis in cancer patients is of diagnostic value as the amount of necrosis is correlated with disease prognosis and it could also be used to predict early efficacy of anti-cancer treatments. In the present study, we identified two near infrared fluorescent (NIRF) carboxylated cyanines, HQ5 and IRDye 800CW (800CW), which possess strong necrosis avidity. In vitro studies showed that both dyes selectively bind to cytoplasmic proteins of dead cells that have lost membrane integrity. Affinity for cytoplasmic proteins was confirmed using quantitative structure activity relations modeling. In vivo results, using NIRF and optoacoustic imaging, confirmed the necrosis avid properties of HQ5 and 800CW in a mouse 4T1 breast cancer tumor model of spontaneous necrosis. Finally, in a mouse EL4 lymphoma tumor model, already 24 h post chemotherapy, a significant increase in 800CW fluorescence intensity was observed in treated compared to untreated tumors. In conclusion, we show, for the first time, that the NIRF carboxylated cyanines HQ5 and 800CW possess strong necrosis avid properties in vitro and in vivo. When translated to the clinic, these dyes may be used for diagnostic or prognostic purposes and for monitoring in vivo tumor response early after the start of treatment.
Highlights
Cell death by necrosis merely occurs under pathological conditions, as a result of physiochemical damage or sudden metabolic failure and is involved in cancer development and treatment [1, 2]
Bioluminescent imaging (BLI) measurements, indicated that no bioluminescent signals were obtained from the dead cells in the center of the well while the surrounding living cells produced strong signals
Our dry ice cell death www.impactjournals.com/oncotarget assay showed a selective staining of dead cells using the carboxylated cyanines HQ5 and 800CW
Summary
Cell death by necrosis merely occurs under pathological conditions, as a result of physiochemical damage or sudden metabolic failure and is involved in cancer development and treatment [1, 2]. Necrosis can be induced by injury caused to tumor tissue by anti-cancer treatments. Therapeutic approaches that initially induce apoptotic cell death often result in secondary necrosis, as a natural outcome of the complete apoptotic program [11]. Accurate quantification of the amount of tissue necrosis has great potential for pre- clinical and clinical applications, especially in monitoring anticancer efficacy at an early stage of treatment instead of at the end of therapy. The long lag- time in determining therapy outcome causes loss of valuable treatment time in non-responding patients that will receive expensive treatment and are unnecessarily exposed to side effects. Evaluation of the therapy efficacy would facilitate the growing call for individualized cancer treatment, allowing the clinician to adjust the therapy based on tumor response, resulting in higher survival rates and cost-efficacy [1, 2]
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