ICS84

Synthesis and charachterization of near-infrared polymeric turn-on nanoprobes for image-guided surgery

Rachel Blau 1 Yana Epshtein 1 Evgeni Pisarevsky 1 Galia Tiram 1 Sahar Israeli Dangoor 1 Eilam Yieni 1 Adva Krivitsky 1 Anat Eldar-Boock 1 Dikla Ben-Shushan 1 Hadas Gibori 1 Anna Scomparin 1 Ori Green 2 Yael Ben-Nun 4 Emmanuelle Merquiol 4 Hila Doron 3 Galia Blum 4 Neta Erez 3 Rachel Grossman 5 Zvi Ram 5 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 Sciences, Tel Aviv University, Tel Aviv, Israel
3Department of Pathology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
4Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel
5Department of Neurosurgery, Tel Aviv Sourasky Medical Center, Tel Aviv University, Tel Aviv, Israel

Complete tumor removal during surgery has a great impact on patient survival. In order to remove the tumor tissue completely with minimal collateral damage to healthy tissues, there is a need for diagnostic tools that will differentiate between the tumor and its normal surroundings [1].

We present here the design, synthesis and characterization of a novel polymeric Turn-ON probe, recently reported by us [2] and composed of N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer bearing self-quenched Cy5 fluorescent dyes. This probe is enzymatically activated by cathepsins, to generate a fluorescent signal. This novel Turn-ON probe was synthesized and characterized in vitro, for its hydrodynamic diameter, quenching, de-quenching, stability, and toxicity properties. Furthermore, in vivo pharmacokinetics and tumor-to-background signal were evaluated in mice bearing orthotopic 4T1 mammary adenocarcinoma tumors. A similar cohort of 4T1 tumor-bearing mice was exploited to evaluate the probe’s utility in image-guided surgery (IGS).

The signal obtained from the tumors during the IGS was stable and delineated the tumor boundaries during the whole surgical procedure, enabling an accurate resection. The control groups that underwent standard surgery under white light only, or under the fluorescence guidance of commercially available ProSense® 680 or 5-Aminolevulinic acid (5-ALA), survived less time and suffered from tumor recurrence earlier than the group that underwent IGS using our Turn-ON probes[3].

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. Blau, et al., Are nanotheranostics and nanodiagnostics-guided drug delivery stepping stones towards precision medicine? Drug Resistance Updates, 2016. 27: p. 39-58.
  2. Ferber*, Baabur-Coher*, Blau* et al., Polymeric nanotheranostics for real-time non-invasive optical imaging of breast cancer progression and drug release. Cancer Lett, 2014.
  3. Blau, et al., Image-guided surgery using near-infrared Turn-ON fluorescent nanoprobes for precise detection of tumor margins. Theranostics, 2018. 8(13): p. 3437-3460.








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