Abstract 1956: ICG pHLIP: A novel agent for fluorescence-guided surgery

Abstract

Abstract Introduction: Fluorescence imaging has applications in medicine for many image-guided procedures such as mapping and visualization of lymph nodes, targeting and marking cancerous lesions and assessment of tumor margins. Several fluorescent molecules are approved for clinical use including the ICG (indocyanine green) near infrared (NIR) fluorescent dye. We conjugated ICG to a pH Low Insertion Peptide (pHLIP®), which senses and targets the acidity at the surfaces of cancer cells, and evaluated ICG pHLIP® as a targeted imaging agent for tumor visualization. Our construct is progressing toward clinical trials. Experimental Procedures: ICG pHLIP® was manufactured for proof-of-concept tumor-targeting imaging studies in mice, and toxicity evaluation in mice, dogs and rats. Tumor targeting was assessed in various human and murine tumor models. Biodistribution was evaluated at different time points from 5 min to 48 hours after a single intravenous administration of 0.5 mg/kg of ICG pHLIP®. The distribution of the agent within tumors was evaluated in tumor sections. Results: The fluorescence of ICG is enhanced about 15 times when pHLIP® tethers it to a cell membrane, significantly improving the contrast index. No toxicity is seen at 25-30x of the proposed human dose, evaluated in mice and dogs. ICG pHLIP® demonstrates excellent tumor targeting, including targeting of 1-3 mm sized tumors in breast. About 10-15% ID/g was observed within tumors at 4 hours p.i., and the signal persists for up to 24 hours with a slight decline at 48 hours. The background signal in major organs decayed after agent administration. The highest uptake, of about 50% ID/g, was observed in liver at 4 hrs p.i. and decayed after that. An excellent correlation was established between ICG pHLIP® NIRF imaging and H&E histopathology at the indicated tumor location. Conclusions: ICG pHLIP® is a promising new imaging agent for fluorescence-guided surgical applications. It is on the path to clinical translation for accurate resection of breast tumors. Since pHLIP® targeting of tumors is based on the general principle of cancer cell surface acidity, ICG pHLIP® is an agent that may be used in a range of fluorescence-guided surgical interventions. Citation Format: Troy Crawford, Anna Moshnikova, Sean Roles, Lukas M. Carter, Jason S. Lewis, Donald M. Engelman, Oleg A. Andreev, Yana K. Reshetnyak. ICG pHLIP: A novel agent for fluorescence-guided surgery [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1956.