ICRS-PAT 2021

Biodegradable polymeric nanoconjugates for melanoma image-guided surgery and therapy

Yana Epshtein 1 Rachel Blau 1,2 Evgeni Pisarevsky 1 Shani Koshrovski-Michael 1 Dikla Ben-Shushan 1 Sabina Pozzi 1 Gal Shenbach-Koltin 1 Lidar Fridrich 1 Adva Krivitsky 1 Ronit Satchi-Fainaro 1
1Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, Israel
2Department of Nano Engineering, University of California, USA

Metastasis to distant organs originated from a primary tumor is a major cause of cancer mortality. Thus, complete primary tumor removal, leaving no residual cancer cells at the incision margins while minimizing the damage to healthy tissue is crucial for patient prognosis. To that end, there is a need for diagnostic tools that will efficiently differentiate between the tumor and its normal surroundings1. Therefore, we designed and synthesized cathepsins (CTS)-sensitive polymeric near-infrared fluorescent (NIRF) Turn-ON ‘smart’ probe which consists of biodegradable polyglutamic acid (PGA) nanocarrier bearing fluorescent dye (Cy5) and dark Black Hole Quencher (BHQ) FRET pair. The probe is nano-sized to enable its selective accumulation at the tumor site, utilizing the enhanced permeability and retention (EPR) effect, known to characterize tumor leaky vasculature. This, together with specific enzymatic activation allowed the NIRF signal to be generated at the tumor site, thus improving the signal-to-noise ratio (SNR). The final quenching level depended on the Cy5 loading and the quencher’s presence when the conjugate bearing Cy5 and BHQ showed better signal silencing than Cy5 homo-FRET. Utilizing an orthotopic melanoma model in immunocompetent mice, we were able to differentiate the tumor by the obtained signal 3 h following iv injection of the probe suggesting its accumulation and successful degradation at the site of interest. Our "smart" polymeric probe proposed herein can potentially assist surgeons’ decision in real-time during surgery regarding the tumor margins needed to be removed, leading to improved patient outcome. Our further study showed that surgery performed by a PGA-based diagnostic system, followed by anticancer treatment with a PGA-based therapeutic system combining two targeted therapy agents, BRAF and MEK inhibitors2 in combination with immune checkpoints inhibitors anti-CTLA4 and anti-PD-1 antibodies decreased the recurrence of primary melanoma, as well as metastasis development and prolonged the survival of the mice.

1Blau R, Epshtein Y, Pisarevsky E et.al. Theranostics 8, 3437-3460 (2018).

2Pisarevsky E, Blau R, Epshtein Y et.al. Advanced Therapeutics 3, 2366-3987 (2020).









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