Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA.
Department of Bioengineering, University of Texas at Dallas, Richardson, TX, 75080, USA.
Adv Sci (Weinh). 2022 Aug;9(24):e2104594. doi: 10.1002/advs.202104594. Epub 2022 Jun 24.
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 -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.
基质过度生成是胰腺导管腺癌（PDAC）的特征，其 5 年生存率为 3%。基质过度生成表现出物理和生化屏障，导致治疗耐药性，然而单独耗竭基质是不成功的，甚至对患者预后有害。本研究首次证明了靶向光激活多抑制剂脂质体（TPMIL），它可以诱导光动力和化学治疗性肿瘤损伤，同时修复原位 PDAC 中的基质过度生成。用西妥昔单抗（抗 EGFR mAb）靶向的 TPMIL 包含脂质化苯并卟啉衍生物（BPD-PC）光敏剂和伊立替康。这些基质过度生成的肿瘤由人 PDAC 细胞和患者来源的癌相关成纤维细胞组成。在光激活后，TPMIL 仅在患者等效剂量纳米脂质体伊立替康（nal-IRI）的 8.1%下就诱导了 90%的肿瘤生长抑制。没有 EGFR 靶向，PMIL 光激活是无效的。与 Visudyne 光动力疗法（PDT）和 nal-IRI 的混合物相比，TPMIL 光激活在抑制肿瘤生长方面的效果也高出六倍，并且还将生存时间延长了两倍以上，无进展生存期延长了五倍以上。二次谐波产生成像显示，TPMIL 光激活将胶原密度降低了>90%，并将胶原非对齐度增加了>10 倍。胶原非对齐度与肿瘤负担的减少和生存时间延长相关。这种单一结构的光毒性、化学治疗和基质过度生成修复方案为显著延长预后不良的患者的生存时间提供了前所未有的机会。
