PD‐L1 Immune Checkpoint Targeted Photoactivable Liposomes (iTPALs) Prime the Stroma of Pancreatic Tumors and Promote Self‐Delivery

Abstract

Desmoplasia in pancreatic ductal adenocarcinoma (PDAC) limits the penetration and efficacy of therapies. We previously showed that photodynamic priming (PDP) using EGFR targeted photoactivable multi‐inhibitor liposomes remediates desmoplasia in PDAC and doubles overall survival. Here, we present bifunctional PD‐L1 immune checkpoint targeted photoactivable liposomes (iTPALs) that mediate both PDP and PD‐L1 blockade. iTPALs also improve phototoxicity in PDAC cells and induce immunogenic cell death. PDP using iTPALs reduces collagen density, thereby promoting self‐delivery by 5.4‐fold in collagen hydrogels, and by 2.4‐fold in syngeneic CT1BA5 murine PDAC tumors. PDP also reduces tumor fibroblast content by 39.4%. Importantly, iTPALs also block the PD‐1/PD‐L1 immune checkpoint more efficiently than free α‐PD‐L1 antibodies. Only a single sub‐curative priming dose using iTPALs provides 54.1% tumor growth inhibition and prolongs overall survival in mice by 42.9%. Overall survival directly correlates with the extent of tumor iTPAL self‐delivery following PDP (Pearson's r = 0.670, P = 0.034), while no relationship was found for sham non‐specific IgG constructs activated with light. When applied over multiple cycles, as is typical for immune checkpoint therapy, PDP using iTPALs promises to offer durable tumor growth delay and significant survival benefit in PDAC patients, especially when used to promote self‐delivery of integrated chemo‐immunotherapy regimens.This article is protected by copyright. All rights reserved

Oxygen-releasing nanodroplets relieve intratumoral hypoxia in head and neck cancer spheroids.

“…56,57 In addition to this, incorporating BPD in the NDs synthesis made the zeta potential even more negative, which was expected given that BPD nanoformulations are generally anionic in nature. 58,59…”

Increasing the Dye Payload of Cetuximab-IRDye800CW Enables Photodynamic Therapy

“…As previously described, anthracene-9,10-dipropionic acid (ADPA) was used as a colorimetric probe at 378 nm to detect singlet oxygen generation. 10 , 20 , 21 While the fluorescence changes in ADPA for singlet oxygen detection are more sensitive than the absorbance changes, absorbance was monitored as to avoid fluorescence artifacts arising from other factors such as contaminants or quenching. 37 It was found that ADPA decreased in absorbance at 378 nm for all samples ( Figure 4 A).…”

“…For SOSG and HPF samples, fluorescence was measured with 460 nm excitation and 530 nm emission (bottom read, 100 gain, 20 μs integration time). ADPA was used as a colorimetric probe for singlet oxygen generation as previously described. ,, The absorbance of ADPA samples was measured at 378 nm (25 flashes, 0 ms settle time).…”

“…ADPA was used as a colorimetric probe for singlet oxygen generation as previously described. 10 , 20 , 21 The absorbance of ADPA samples was measured at 378 nm (25 flashes, 0 ms settle time).…”

A Physiochemical, In Vitro, and In Vivo Comparative Analysis of Verteporfin–Lipid Conjugate Formulations: Solid Lipid Nanoparticles and Liposomes

“…Our prior work has demonstrated that lipid-anchoring of BPD markedly reduces its leakage from liposomes and enables codelivery of multiple agents. 14,15,18,27,28 In addition to local tumor ablation, PDT can also induce immunogenic cell death (ICD) through the release of damageassociated molecular patterns (DAMPs) such as calreticulin, heat shock protein (HSP) 60, HSP 70, and high mobility group box 1 (HMGB1). 29−31 A study by De Silva et al demonstrated the membrane translocation of ICD markers following PDT with a triple-receptor targeted liposomal formulation of BPD in an in vitro heterocellular 3D model of pancreatic tumors.…”