Towards Photodynamic Image-Guided Surgery of Head and Neck Tumors: Photodynamic Priming Improves Delivery and Diagnostic Accuracy of Cetuximab-IRDye800CW

Abstract

Fluorescence image-guided surgery (IGS) using antibody conjugates of the fluorophore IRDye800CW have revolutionized the surgical debulking of tumors. Cetuximab, an anti-epidermal growth factor receptor (EGFR) monoclonal antibody, conjugated to IRDye800CW (Cet-IRDye800) is the first molecular targeted antibody probe to be used for IGS in head and neck cancer patients. In addition to surgical debulking, Cetuximab-targeted photodynamic therapy (photoimmunotherapy; PIT) is emerging in the clinic as a powerful modality for head and neck tumor photodestruction. A plethora of other photoactivable agents are also in clinical trials for photodynamic-based therapies of head and neck cancer. Considering the vascular and stromal modulating effects of sub-therapeutic photodynamic therapy, namely photodynamic priming (PDP), this study explores the potential synergy between PDP and IGS for a novel photodynamic image-guided surgery (P-IGS) strategy. To the best of our knowledge, this is the first demonstration that PDP of the tumor microenvironment can augment the tumor delivery of full-length antibodies, namely Cet-IRDye800. In this study, we demonstrate a proof-of-concept that PDP primes orthotopic FaDu human head and neck tumors in mice for P-IGS by increasing the delivery of Cet-IRDye800 by up to 138.6%, by expediting its interstitial accumulation by 10.5-fold, and by increasing its fractional tumor coverage by 49.5% at 1 h following Cet-IRDye800 administration. Importantly, PDP improves the diagnostic accuracy of tumor detection by up to 264.2% with respect to vicinal salivary glands at 1 h. As such, PDP provides a time-to-surgery benefit by reducing the time to plateau 10-fold from 25.7 h to 2.5 h. We therefore propose that a pre-operative PDP regimen can expedite and augment the accuracy of IGS-mediated surgical debulking of head and neck tumors and reduce the time-to-IGS. Furthermore, this P-IGS regimen, can also enable a forward-looking post-operative protocol for the photodestruction of unresectable microscopic disease in the surgical bed. Beyond this scope, the role of PDP in the homogenous delivery of diagnostic, theranostic and therapeutic antibodies in solid tumors is of considerable significance to the wider community.

Increasing the Dye Payload of Cetuximab-IRDye800CW Enables Photodynamic Therapy

“…Cet-IRDye800CW was made in accordance with our previous paper . Briefly, Cetuximab (ERBITUX, Eli Lilly, 2 mg·mL –1 ) was conjugated to IRDye800CW (LI-COR) through amide coupling.…”

“…Cet-IRDye800CW was made in accordance with our previous paper. 19 Briefly, Cetuximab (ERBITUX, Eli Lilly, 2 mg·mL –1 ) was conjugated to IRDye800CW (LI-COR) through amide coupling. A 10 mg·mL –1 stock solution of IRDye800CW-NHS ester in anhydrous dimethyl sulfoxide (DMSO, Sigma-Aldrich) was prepared and added to Cetuximab (500 μL aliquots, 2 mg·mL –1 , phosphate buffer) in 2.5-fold, 10-fold, and 20-fold molar excess.…”

Shedding Light on Chemoresistance: The Perspective of Photodynamic Therapy in Cancer Management

“…This elegant work showed that PDP could notably enhance the loaded chemo agents' accumulation in the treated tumor compared to the control, hence increasing the therapeutic outcomes and reducing the long-term normal toxicity. A similar approach was also assessed by C. Bhandari et al [57] in a study in which they evaluated the delivery of a cetuximab-IRdye800 conjugate in orthotopic head-and-neck cancer after PDP. The tumor accumulation of the dye-conjugated antibody was increased by up to 138.6 ± 47.3% within 1 h of intravenous administration when the tumor had been subjected to PDP.…”

Nanotheranostics-based Management of Head and Neck Cancer

“…This approach helps to remove the tumor through the surgical method after detecting its accurate position. Adopted by CC by 4 from 29 .…”