Image-Guided Surgery using Near-Infrared Turn-On Nanoprobes for Precise Detection of Tumor Margins

Rachel Blau rachelniss@gmail.com 1 Yana Epshtein 1 Galia Tiram 1 Evgeni Pisarevsky 1 Sahar Israeli 1 Eilam Yeini 1 Adva Krivitsky 1 Anat Eldar-Boock 1 Dikla Ben-Shushan 1 Ori Green 2 Yael Ben-Nun 3 Emmanuelle Merquiol 3 Hila Schwartz 4 Galia Blum 3 Neta Erez 4 Doron Shabat 2 Ronit Satchi-Fainaro 1
1Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
2Department of Organic Chemistry, School of Chemistry, Raymond and Beverly Sackler Faculty of Exact Science, Tel Aviv University, Tel Aviv, Israel
3School of Pharmacy, The Institute for Drug Research, Faculty of Medicine, Campus Ein Kerem, The Hebrew University of Jerusalem, Jerusalem, Israel
4Department of Pathology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

Complete tumor removal during surgery has a great impact on patient survival rate. 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.

We present here the design, synthesis and characterization of three polymeric Turn-ON probes activated by cathepsin B enzymatic degradation to generate a fluorescent signal. Two polymeric backbones are composed of biodegradable poly-L-glutamic acid (PGA) polymer, loaded with self-quenched (homo-FRET) near-infrared (NIR) Cy5 molecules or hetero-FRET-quenched Cy5 and dark quencher moieties. The third polymeric Turn-ON probe was recently reported by us1 and composed of N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer bearing self-quenched Cy5 fluorescent dyes.

We studied the kinetics of the polymeric nano-probe on orthotopic breast cancer model in mice and showed an improved tumor-to-background ratio. The signal obtained from the tumor was stable and delineated the tumor boundaries during the whole surgical procedure, enabling a more accurate resection. The polymeric probes were characterized for their diameter, quenching and Turn-ON properties. The control group of tumor-bearing mice, that underwent standard surgery with no fluorescence real-time guidance, survived less time and suffered from tumor recurrence earlier than the group that underwent image-guided surgery (IGS) using our Turn-ON probes2.

This “smart” polymeric Turn-ON probe can potentially assist surgeons to decide in real time during surgery regarding the tumor margins needed to be removed leading to improved patient outcome.

REFERENCES

  1. Ferber S, Baabur-Cohen H, Blau R, et al. Polymeric nanotheranostics for real-time non-invasive optical imaging of breast cancer progression and drug release. Cancer Lett. Mar 12 (2014).
  2. Blau R, Epshtein Y, Tiram G, et al., Image-Guided Surgery Using Near Infrared Turn-ON Fluorescent Nanoprobes for Precise Detection of Tumor Margins, under review (2017).








Powered by Eventact EMS