Remediating Desmoplasia with EGFR-Targeted Photoactivable Multi-Inhibitor Liposomes Doubles Overall Survival in Pancreatic Cancer.
Remediating Desmoplasia with EGFR-Targeted Photoactivable Multi-Inhibitor Liposomes Doubles Overall Survival in Pancreatic Cancer.
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DOI：
10.1002/advs.202104594
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发表时间：
2022-08
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结缔组织增生是胰腺导管腺癌（PDAC）的特征，其5年生存率为3%。结缔组织增生存在导致治疗抵抗的物理和生物化学障碍，但单独消耗基质是不成功的，甚至对患者的结果有害。本研究首次证明了靶向光活化多抑制剂脂质体（TPMIL）可诱导光动力学和化疗肿瘤损伤，同时治疗原位PDAC中的结缔组织增生。西妥昔单抗（抗EGFR mAb）靶向TPMIL含有脂化苯并卟啉衍生物（BPD-PC）光敏剂和伊立替康。促结缔组织增生性肿瘤包括人PDAC细胞和患者来源的癌症相关成纤维细胞。光活化后，TPMIL仅在患者等效剂量的8.1%的纳米脂质体伊立替康（nal-IRI）下诱导90%的肿瘤生长抑制。没有EGFR靶向，PMIL光活化是无效的。TPMIL光活化在抑制肿瘤生长方面比Visudyne-光动力疗法（PDT）和nal-IRI的混合物有效六倍，并且还使生存期增加一倍，无进展生存期延长五倍以上。二次谐波成像显示，TPMIL光活化使胶原蛋白密度降低>90%，并使胶原蛋白非对齐增加>103倍。胶原蛋白不对齐与肿瘤负荷和存活率的降低相关。这种单一结构的光毒性、化疗和结缔组织增生治疗方案为大幅延长其他令人沮丧的肿瘤患者的生存期提供了前所未有的机会。胰腺导管腺癌（PDAC）中的结缔组织增生是有效治疗该病的最重要障碍之一。单独治疗结缔组织增生在临床上已被证明是不成功的，因此需要变革性的组合方法。这项研究首次证明了使用单一靶向和可活化的光动力化疗构建体的结缔组织增生修复方案使原位PDAC的总生存期增加一倍。
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. Desmoplasia in pancreatic ductal adenocarcinoma (PDAC) is one of most significant hurdles in effective management of the disease. Treating desmoplasia alone has proven to be unsuccessful in the clinic, thus necessitating transformative combination approaches. This study is the first to demonstrate that a desmoplasia‐remediating regimen using a single targeted and activable photodynamic‐chemotherapeutic construct doubles overall survival in orthotopic PDAC.