Image-guided surgery using near-infrared Turn-ON fluorescent nanoprobes for precise detection of tumor margins

Abstract

Complete tumor removal during surgery has a great impact on patient survival. To that end, the surgeon should detect the tumor, remove it and validate that there are no residual cancer cells left behind. Residual cells at the incision margin of the tissue removed during surgery are associated with tumor recurrence and poor prognosis for the patient. In order to remove the tumor tissue completely with minimal collateral damage to healthy tissue, there is a need for diagnostic tools that will differentiate between the tumor and its normal surroundings.Methods: We designed, synthesized and characterized three novel polymeric Turn-ON probes that will be activated at the tumor site by cysteine cathepsins that are highly expressed in multiple tumor types. Utilizing orthotopic breast cancer and melanoma models, which spontaneously metastasize to the brain, we studied the kinetics of our polymeric Turn-ON nano-probes.Results: To date, numerous low molecular weight cathepsin-sensitive substrates have been reported, however, most of them suffer from rapid clearance and reduced signal shortly after administration. Here, we show an improved tumor-to-background ratio upon activation of our Turn-ON probes by cathepsins. The signal obtained from the tumor was stable and delineated the tumor boundaries during the whole surgical procedure, enabling accurate resection.Conclusions: Our findings show that the control groups of tumor-bearing mice, which underwent either standard surgery under white light only or under the fluorescence guidance of the commercially-available imaging agents ProSense® 680 or 5-aminolevulinic acid (5-ALA), survived for less time and suffered from tumor recurrence earlier than the group that underwent image-guided surgery (IGS) using our Turn-ON probes. Our "smart" polymeric probes can potentially assist surgeons' decision in real-time during surgery regarding the tumor margins needed to be removed, leading to improved patient outcome.

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“…2019, 31,1904329 HFR-eNPs 565-700 nm [128] 2018 NanoCy7.5 100k-PBA 800-900 nm [129] OTL38 793 nm [130] Turn-ON probes 670 nm [131] 2019 THQ-Rosol 710 nm [132] RVG&IRDye800-Gd2O3 TNs 806 nm [133] SWNT-CY7-IGF-1Ra 770 nm [134] www.advmat.de www.advancedsciencenews.com Adv. Mater.…”

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“…However, an advantage of the use of fluorescent probes for imaging is that they can be engineered to be activated through specific molecular pathways. This will lead to personalization of the imaging methodology according to the patient's specific biomarkers [27].…”

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