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

Abstract

Desmoplasia is characteristic of pancreatic ductal adenocarcinoma (PDAC), which exhibits 5‐year survival rates of 3%. Desmoplasia presents physical and biochemical barriers that contribute to treatment resistance, yet depleting the stroma alone is unsuccessful and even detrimental to patient outcomes. This study is the first demonstration of targeted photoactivable multi‐inhibitor liposomes (TPMILs) that induce both photodynamic and chemotherapeutic tumor insult, while simultaneously remediating desmoplasia in orthotopic PDAC. TPMILs targeted with cetuximab (anti‐EGFR mAb) contain lipidated benzoporphyrin derivative (BPD‐PC) photosensitizer and irinotecan. The desmoplastic tumors comprise human PDAC cells and patient‐derived cancer‐associated fibroblasts. Upon photoactivation, the TPMILs induce 90% tumor growth inhibition at only 8.1% of the patient equivalent dose of nanoliposomal irinotecan (nal‐IRI). Without EGFR targeting, PMIL photoactivation is ineffective. TPMIL photoactivation is also sixfold more effective at inhibiting tumor growth than a cocktail of Visudyne‐photodynamic therapy (PDT) and nal‐IRI, and also doubles survival and extends progression‐free survival by greater than fivefold. Second harmonic generation imaging reveals that TPMIL photoactivation reduces collagen density by >90% and increases collagen nonalignment by >103‐fold. Collagen nonalignment correlates with a reduction in tumor burden and survival. This single‐construct phototoxic, chemotherapeutic, and desmoplasia‐remediating regimen offers unprecedented opportunities to substantially extend survival in patients with otherwise dismal prognoses.

Culprits of PDAC resistance to gemcitabine and immune checkpoint inhibitor: Tumour microenvironment components

“…Another randomized clinical trial (NCT02030860) evaluated neoadjuvant paricalcitol with GEM/Nab-PTX in resectable PDAC patients. In addition to VDR signaling activation, photodynamic therapy (PDT) has also been reported to decrease ECM density, increase collagen nonalignment, and improve drug delivery ( Obaid et al, 2019 ; Obaid et al, 2022 ). Patients who are refractory to GEM require high-dose administration, but intolerable toxicities are major concerns.…”

Overview of Nanoparticle-Based Approaches for the Combination of Photodynamic Therapy (PDT) and Chemotherapy at the Preclinical Stage

“…However, very recently, Obaid and collaborators [ 110 ] reported on the synthesis of a single nanosystem (e.g., a cetuximab antibody-targeted liposome (EGFR-TPMIL)) for the co-delivery of IRI and a lipidated version of BPD for the concomitant pancreatic ductal adenocarcinoma (PDAC) treatment and associated desmoplasia remediation. Indeed, using MIA PaCa-2 cells as an in vitro PDAC model, the authors demonstrated that cetuximab-conjugated TPMIL increased up to 34-folds of the specificity of liposome binding to EGFR-overexpressing cells with respect to the untargeted counterpart (PMIL), thus confirming the tumor specificity of the targeted nanoconstruct as well as the exceptional photo-toxic effect determined after a 690 nm light cells activation (IC 50 measured for TPMIL decreased by 21-folds with respect to that for untargeted PMIL).…”

Recent advances in photothermal therapy-based multifunctional nanoplatforms for breast cancer

“…Photodynamic therapy (PDT) has been demonstrated as a minimally invasive method to treat various types of cancer, including breast cancer, melanoma, and lung cancer ( Tang et al, 2021 ; Ding et al, 2022 ; Jia et al, 2022 ; Obaid et al, 2022 ; Pan et al, 2022 ; Zhang et al, 2022 ). The photosensitizers can be activated under a light source to generate reactive oxygen species (ROS) to kill cancer cells.…”