{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Obaid G"],"funding":["Irish Research Council","Science Foundation Ireland","NCI NIH HHS","National Institutes of Health","NIH HHS","Bullock-Wellman Fellowship"],"pagination":["e2104594"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC9404396"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["9(24)"],"pubmed_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 >10<sup>3</sup> -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."],"journal":["Advanced science (Weinheim, Baden-Wurttemberg, Germany)"],"pubmed_title":["Remediating Desmoplasia with EGFR-Targeted Photoactivable Multi-Inhibitor Liposomes Doubles Overall Survival in Pancreatic Cancer."],"pmcid":["PMC9404396"],"funding_grant_id":["R01 CA156177","S10 OD012326","GOIPG/2016/1250","P01CA084203","IvP 13/IA/1894","S10OD012326","P01 CA084203","R01 CA160998","R01CA160998","K99 CA215301","R00CA215301","R01CA156177","R00 CA215301","K99CA215301"],"pubmed_authors":["Wu J","Jin W","Shah N","Swain JWR","Mino-Kenudson M","McFarland SA","Vangel M","Stoilova-McPhie S","Ding X","Hasan T","Thomsen H","Lin C","Callaghan S","Bano S","Cameron CG","Zhao J","Obaid G"],"additional_accession":[]},"is_claimable":false,"name":"Remediating Desmoplasia with EGFR-Targeted Photoactivable Multi-Inhibitor Liposomes Doubles Overall Survival in Pancreatic Cancer.","description":"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 >10<sup>3</sup> -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.","dates":{"release":"2022-01-01T00:00:00Z","publication":"2022 Aug","modification":"2024-10-16T04:13:38.037Z","creation":"2024-10-16T04:13:38.037Z"},"accession":"S-EPMC9404396","cross_references":{"pubmed":["35748165"],"doi":["10.1002/advs.202104594"]}}