Near-infrared (NIR)-activable liposomes containing photosensitizer (PS)-lipid conjugates are emerging as tunable, high-payload, and tumor-selective platforms for photodynamic therapy (PDT)-based theranostics. To date, the impact that the membrane composition of a NIR-activable liposome (the chemical nature and subsequent conformation of PS-lipid conjugates) has on their in vitro and in vivo functionality has not been fully investigated. While their chemical nature is critical, the resultant physical conformation dictates their interactions with the immediate biological environments. Here, we evaluate NIR-activable liposomes containing lipid conjugates of the clinically-used PSs benzoporphyrin derivative (BPD; hydrophobic, membrane-inserting conformation) or IRDye 700DX (hydrophilic, membrane-protruding conformation) and demonstrate that membrane composition is critical for their function as tumor-selective PDT-based platforms. The PS-lipid conformations were primarily dictated by the varying solubilities of the two PSs and assisted by their lipid conjugation sites. Conformation was further validated by photophysical analysis and computational predictions of PS membrane partitioning (topological polar surface area [tPSA], calculated octanol/water partition [cLogP], and apparent biomembrane permeability coefficient [Papp]). Results show that the membrane-protruding lipo-IRDye700DX exhibits 5-fold more efficient photodynamic generation of reactive molecular species (RMS), 12-fold expedited phototriggered burst release of entrap-ped agents, and 15-fold brighter fluorescence intensity as compared to the membrane-inserting lipo-BPD-PC (phosphatidylcholine conjugate). Although the membrane-inserting lipo-BPD-PC exhibits less efficient photo-dynamic generation of RMS, it allows for more sustained phototriggered release, 10-fold greater FaDu cancer cell phototoxicity, and 7.16-fold higher tumor-selective delivery in orthotopic mouse FaDu head and neck tumors. These critical insights pave the path for the rational design of emerging NIR-activable liposomes, whereby functional consequences of membrane composition can be tailored toward a specific therapeutic purpose.
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.
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