PEI-Engineered Respirable Particles Delivering a Decoy Oligonucleotide to NF-κB: Inhibiting MUC2 Expression in LPS-Stimulated Airway Epithelial Cells

A specific and promising approach to limit inflammation and mucin iperproduction in chronic lung diseases relies on specific inhibition of nuclear Factor-κB (NF-κB) by a decoy oligonucleotide (dec-ODN). To fulfill the requirements dictated by translation of dec-ODN therapy in humans, inhalable dry powders were designed on a rational basis to provide drug protection, sustained release and to optimize pharmacological response. To this end, large porous particles (LPP) for dec-ODN delivery made of a sustained release biomaterial (poly(lactic-co-glycolic) acid, PLGA) and an “adjuvant” hydrophilic polymer (polyethylenimine, PEI) were developed and their effects on LPS-stimulated human airway epithelial cells evaluated. The composite PLGA/PEI particles containing dec-ODN (i.e., LPPPEI) were successfully engineered for widespread deposition in the lung and prolonged release of intact dec-ODN in vitro. LPPPEI caused a prolonged inhibition of IL-8 and MUC2 expression in CF human bronchial epithelial cells and human epithelial pulmonary NCI-H292 cells, respectively, as compared to naked dec-ODN. Nonetheless, as compared to previously developed LPP, the presence of PEI was essential to construct a dec-ODN delivery system able to act in mucoepidermoid lung epithelial cells. In perspective, engineering LPP with PEI may become a key factor for tuning carrier properties, controlling lung inflammation and mucin production which, in turn, can foster in vivo translation of dec-ODN therapy.

在慢性肺部疾病中，限制炎症与黏蛋白过度生成的一种特异性且极具前景的策略，依赖于通过诱饵寡核苷酸（decoy oligonucleotide, dec-ODN）对核因子κB（nuclear Factor-κB, NF-κB）的特异性抑制。为满足dec-ODN疗法向人类临床转化的相关要求，研究人员基于理性设计思路开发了可吸入干粉制剂，以实现药物保护、缓释效果并优化药理响应。为此，研究人员开发了由缓释生物材料聚乳酸-羟基乙酸共聚物（poly(lactic-co-glycolic) acid, PLGA）与“佐剂”亲水性聚合物聚乙烯亚胺（polyethylenimine, PEI）制成的、用于递送dec-ODN的大型多孔颗粒（large porous particles, LPP），并评估了其对脂多糖刺激的人气道上皮细胞的作用效果。含dec-ODN的PLGA/PEI复合颗粒（即LPPPEI）已被成功构建，可在肺部实现广泛沉积，并在体外实现完整dec-ODN的长效释放。与裸露的dec-ODN相比，LPPPEI可分别在囊性纤维化（cystic fibrosis, CF）人支气管上皮细胞以及人肺上皮NCI-H292细胞中，实现对白细胞介素8（IL-8）与黏蛋白2（MUC2）表达的长效抑制。然而，相较于此前开发的LPP，PEI的存在对于构建可在黏液表皮样肺部上皮细胞中发挥作用的dec-ODN递送系统至关重要。从研究前景来看，利用PEI修饰LPP或可成为调控载体特性、控制肺部炎症与黏蛋白生成的关键因素，进而推动dec-ODN疗法向体内应用的转化。