Membrane composition is a functional determinant of NIR-activable liposomes in orthotopic head and neck cancer

Abstract

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.

Remediating Desmoplasia with EGFR‐Targeted Photoactivable Multi‐Inhibitor Liposomes Doubles Overall Survival in Pancreatic Cancer

“…This is not unexpected, as we have previously shown that liposomes containing phospholipid conjugates of PSs accumulate in endolysosomal compartments both with and without receptor targeting. [14,33,37,38] Immediately following 690 nm photodynamic activation with 40 J cm −2 , the TPMIL constructs destabilized, which progressed for 5 days following irradiation, suggesting irreversible bilayer disruption as a mechanism for phototriggered irinotecan release (Figure S3a,b, Supporting Information). Phototriggered irinotecan release from the TPMIL constructs in 10% FBS solutions at 37 °C was quantified using LC-MS/MS upon 40 J cm −2 photodynamic activation with 690 nm light (Figure S3c-e, Supporting Information).…”

“…These findings are also consistent with our prior work where we have shown that phototriggered release of the small molecule inhibitor cabozantinib and the water soluble fluorophore calcein disodium salt using BPD and BPD-PC embedded liposomes is an entirely photochemical process. [14,36,37] The in vitro (photo)therapeutic efficacy of the constructs in MIA PaCa-2 cells is summarized in Table S2, Supporting Information. Results show that without light, the TPMIL construct (IC 50 = 237.07 ± 75.64 nm) provides a 4.9-fold greater degree of cytotoxicity, as compared to the untargeted PMIL construct (IC 50 = 1167.67 ± 256.54 nm).…”

“…This is not unexpected, as we have previously shown that liposomes containing phospholipid conjugates of PSs accumulate in endolysosomal compartments both with and without receptor targeting. [ 14,33,37,38 ]…”

“…These findings are also consistent with our prior work where we have shown that phototriggered release of the small molecule inhibitor cabozantinib and the water soluble fluorophore calcein disodium salt using BPD and BPD‐PC embedded liposomes is an entirely photochemical process. [ 14,36,37 ]…”

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

“…Cells were cultured in DMEM (Corning) containing 10% Fetal Bovine Serum (R&D Systems). 7.5 x 10 5 FaDu cells suspended in 20 μl sterile 1X DPBS were implanted orthotopically transcervically into the floor of the mouth according to previously published procedures ( 28 , 29 ). 15 d following tumor implantation, the tumors reached a diameter of ca.…”