Purpose: Chronic pancreatitis (CP) is an inflammatory disorder of the pancreas that leads to impaired pancreatic function. The limited therapeutic options and the lack of molecular targeting ligands or non-serum-based biomarkers hinder the development of target-specific drugs. Thus, there is a need for an unbiased, comprehensive discovery and evaluation of pancreatitis-specific ligands.
Methods: This study utilized a computational-guided in vivo phage display approach to select peptide ligands selective for cellular components in the caerulein-induced mouse model of CP. The identified peptides were conjugated to pegylated DOPC liposomes via the reverse-phase evaporation method, and the in vivo specificity and pharmacokinetics were determined. As proof of concept, CP-targeted liposomes were used to deliver an antifibrotic small molecular drug, apigenin. Antifibrotic effects determined by pancreatic histology, fibronectin expression, and collagen deposition were evaluated.
Results: We have identified five peptides specific for chronic pancreatitis and demonstrated selectivity to activated pancreatic stellate cells, acinar cells, macrophages, and extracellular matrix, respectively. MDLSLKP-conjugated liposomes demonstrated an increased particle accumulation by 1.3-fold in the inflamed pancreas compared to the control liposomes. We also observed that targeted delivery of apigenin resulted in improved acini preservation, a 37.2% and 33.1% respective reduction in collagen and fibronectin expression compared to mice receiving the free drug, and reduced oxidative stress in the liver.
Conclusion: In summary, we have developed a systematic approach to profile peptide ligands selective for cellular components of complex disease models and demonstrated the biomedical applications of the identified peptides to improve tissue remodeling in the inflamed pancreas.

Keywords: phage display, next-generation sequencing, peptide ligands, targeted liposomes, drug delivery


中文翻译：

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慢性胰腺炎靶向抗纤维化治疗新配体的鉴定

目的：慢性胰腺炎（CP）是一种胰腺炎性疾病，会导致胰腺功能受损。有限的治疗选择和缺乏分子靶向配体或非血清生物标志物阻碍了靶向特异性药物的开发。因此，需要对胰腺炎特异性配体进行公正、全面的发现和评估。
方法：本研究利用计算引导的体内噬菌体展示方法来选择对雨蛙素诱导的 CP 小鼠模型中的细胞成分具有选择性的肽配体。将鉴定出的肽通过反相蒸发法与聚乙二醇化 DOPC 脂质体结合，并测定体内特异性和药代动力学。作为概念验证，CP 靶向脂质体被用于递送抗纤维化小分子药物芹菜素。评估了由胰腺组织学、纤连蛋白表达和胶原沉积确定的抗纤维化作用。
结果：我们已经鉴定出五种特异性针对慢性胰腺炎的肽，并分别证明了对活化的胰腺星状细胞、腺泡细胞、巨噬细胞和细胞外基质的选择性。与对照脂质体相比，MDLSLKP 缀合的脂质体在发炎的胰腺中的颗粒积累增加了 1.3 倍。我们还观察到，与接受游离药物的小鼠相比，靶向递送芹菜素可改善腺泡保存，胶原蛋白和纤连蛋白表达分别减少 37.2% 和 33.1%，并减少肝脏中的氧化应激。
结论：总之，我们开发了一种系统方法来分析对复杂疾病模型的细胞成分具有选择性的肽配体，并证明了所鉴定的肽在改善发炎胰腺组织重塑方面的生物医学应用。

关键词：噬菌体展示，二代测序，肽配体，靶向脂质体，药物递送