Is seeing believing?—signal differentiation in a preclinical transbronchial imaging study implementing a composite optical fiber bronchoscope to detect a folate receptor-targeted near-infrared fluorophore

Background: There is a significant unmet clinical need for accurate target identification in diagnosis and treatment of malignant tumors, including lung cancer. Optical imaging, specifically fluorescence-based, enables real-time tracking during endoscopic or surgical procedures. Here, we aim to investigate the scenario in which the fluorescence signal is possibly not due to the presence of the administered fluorescent agent, using a preclinical transbronchial lung cancer model. Methods: Pafolacianine is a folate analog conjugated with an indocyanine green-like dye (peak excitation 774–776 nm, detection 794–796 nm). A composite optical fiberscope (COF) with 0.97 mm outer diameter tip was used for laser excitation at 776 nm and imaging. Spectrometer measurements along the same optical axis as the COF were also made to characterize the signal. In a mouse xenograft model, human folate receptor-positive KB tumor cells were inoculated subcutaneously into the flank of immunodeficient (NCr-Foxn1nu) mice and grown to 8–15 mm diameter. The mice were then infused with 0.025 or 0.25 mg/kg pafolacianine or negative control. At 24 hours after infusion, tumor and contralateral background spectral measurements were acquired using both the COF imaging system and the spectrometer. In a swine peribronchial model, a pafolacianine-infused tumor was placed manually on the outer wall of the swine bronchus by forceps. The COF was inserted into the working channel of a bronchoscope, which was then inserted through an endotracheal tube and navigated close to where the tumor was located. While changing the distance from the COF tip to the bronchial mucosa, transbronchial COF imaging and spectroscopic measurements were acquired separately. Results: In the in vivo mouse xenograft model, we observed a peak in the spectrometer spectrum at 810 nm that was more intense in the 0.25 mg/kg cohort than in the 0.025 mg/kg pafolacianine cohort. In the swine peribronchial tumor model with negative control tumor, we observed the excitation laser signal (776 nm) with the spectrometer when the COF tip was placed in very close (~1 mm) proximity to the bronchial mucosa but this signal was not detected at 5 or 10 mm distance. Conclusions: In situations of very close proximity of the COF to the bronchial wall (~1 mm), we detected both excitation and emission signals. When the distance was increased slightly, only the fluorescence emission signal was detected. Although these results are not fully generalizable to all fluorescence bronchoscopy settings, it is important for clinicians to be aware of possible limitations in the filter rejection of excitation light leakage and to avoid extreme proximity between the bronchial mucosa and the fiber tip. We report this to exemplify artefacts that can occur in fluorescence bronchoscopy.

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