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222. Transbronchial Lung Tumor Localization with Folate Receptor-Targeted Near-Infrared Molecular Imaging: A Proof of Concept Study in Animal Models

May 17, 2022

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OBJECTIVE: To improve the diagnostic yield of bronchoscopy, a variety of navigation bronchoscopy techniques have been developed, especially for lesions located outside of the bronchial lumen. Our objective was to do a preclinical assessment of folate receptor (FR)-targeted near-infrared (NIR) imaging-guided bronchoscopy to detect peribronchial tumors.

METHODS: Pafolacianine was used as a NIR fluorescent imaging agent (peak excitation and emission wavelengths, 774-776/794-796 nm). Pafolacianine is a folate analog conjugated with an indocyanine green-like dye. A FRα-positive human cervical carcinoma cell line (KB) was used for in vivo experiments to assess fluorescent brightness, pharmacokinetics, and biodistribution. An ultra-thin composite optical fiberscope (UCF) with a 0.97 mm outer diameter tip was used for laser irradiation and fluorescence imaging. Laser excitation through the UCF was performed at 50-75 mW using a 776 nm laser source. A NIR camera system with an 800 nm long-pass filter served as the detector. UCF parameters were evaluated using serial dilutions of pafolacianine. Tumor-to-background ratio (TBR) was calculated by the fluorescence intensity value acquired by the camera system and validated using a separate overhead spectral imaging system. Two animal models were used: 1) KB tumor in immunodeficient mice created by inoculating subcutaneously with KB cells and mice were infused intravenously with 0.05 mg/kg, 0.025 mg/kg of pafolacianine; and 2) ex vivo swine lungs into which pafolacianine-laden KB tumor tissue was transplanted at various peribronchial sites. Tumors for this latter model were resected at the time of peak TBR (24 hrs post injection).

RESULTS: The UCF system could visualize the fluorescence of pafolacianine at concentration of ≥ 0.5 µM at a distance of ≤ 10 mm. With the in vivo murine model, TBR peaked at 24 hrs post-pafolacianine injection by UCF (TBR: 2.6 at 0.05 mg/kg, 2.0 at 0.025 mg/kg) and confirmed by spectral imaging. The fluorescence signal intensity was significantly different between normal lung parenchyma and KB tumors post-mortem. In ex vivo swine lungs with transplanted pafolacianine-laden tumors (collected 24 hrs post-pafolacianine injection), the UCF could successfully detect transbronchial tumor fluorescence (tumors from 0.05 mg/kg of pafolacianine infused mice detected at the carina and peripheral airway, tumor from 0.025 mg/kg of pafolacianine infused mice detected only in the periphery).

CONCLUSIONS: Pafolacianine-laden FR-positive tumors were transbronchially detected by NIR fluorescence imaging in ex vivo swine lungs. Molecular-targeted NIR-guided bronchoscopy may enhance the transbronchial localization of certain tumors, which may facilitate more accurate bronchoscopic sampling. Further in vivo preclinical assessments are needed to confirm the feasibility of this technology.

Tsukasa Ishiwata (1), Nicholas Bernards (1), Yoshihisa Hiraishi (1), Yuki Sata (1), Alexander Gregor (1), Masato Aragaki (1), Kazuhiro Yasufuku (1), (1) Division of Thoracic Surgery, Toronto General Hospital, Toronto, ON

Sunil Singhal

Invited Discussant

Sunil Singhal MD is the William Maul Measey Professor in the Department of Surgery at the University of Pennsylvania Perelman School of Medicine, Chief of the Division of Thoracic Surgery, and the Vice Chair for Translational Research for the Department of Surgery.

Tsukasa Ishiwata

Abstract Presenter

Dr. Ishiwata is an interventional pulmonologist and a clinical fellow in the Division of Thoracic Surgery at Toronto General Hospital, Canada. He is interested in the early diagnosis and treatment of lung cancer. His current research is about establishing a safe bronchoscopic treatment for lung cancer by the development of novel bronchoscopic device and nanoparticle-based photosensitizer for lung phototherapy.