Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, the State University of New Jersey, Piscataway, NJ 08854, United States.
Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, the State University of New Jersey, Piscataway, NJ 08854, United States.
J Control Release. 2019 Feb 28;296:225-231. doi: 10.1016/j.jconrel.2019.01.025. Epub 2019 Jan 21.
Cystic fibrosis (CF), a most deadly genetic disorder, is caused by mutations of CF transmembrane receptor (CFTR) - a chloride channel present at the surface of epithelial cells. In general, two steps have to be involved in treatment of the disease: correction of cellular defects and potentiation to further increase channel opening. Consequently, a combinatorial simultaneous treatment with two drugs with different mechanisms of action, lumacaftor and ivacaftor, has been recently proposed. While lumacaftor is used to correct p.Phe508del mutation (the loss of phenylalanine at position 508) and increase the amount of cell surface-localized CFTR protein, ivacaftor serves as a CFTR potentiator that increases the open probability of CFTR channels. Since the main organ that is affected by cystic fibrosis is the lung, the delivery of drugs directly to the lungs by inhalation has a potential to enhance the efficacy of the treatment of CF and limit adverse side effects upon healthy tissues and organs. Based on our extensive experience in inhalation delivering of drugs by different nanocarriers, we selected nanostructured lipid carriers (NLC) for the delivery both drugs directly to the lungs by inhalation and tested NLC loaded with drugs in vitro (normal and CF human bronchial epithelial cells) and in vivo (homozygote/homozygote bi-transgenic mice with CF). The results show that the designed NLCs demonstrated a high drug loading efficiency and were internalized in the cytoplasm of CF cells. It was found that NLC-loaded drugs were able to restore the expression and function of CFTR protein. As a result, the combination of lumacaftor and ivacaftor delivered by lipid nanoparticles directly into the lungs was highly effective in treating lung manifestations of cystic fibrosis.
囊性纤维化（CF）是一种最致命的遗传性疾病，由 CF 跨膜受体（CFTR）的突变引起 - 一种存在于上皮细胞表面的氯离子通道。一般来说，治疗这种疾病需要涉及两个步骤：纠正细胞缺陷和增强以进一步增加通道开放。因此，最近提出了一种联合使用两种具有不同作用机制的药物 - 拉卡弗托和伊伐卡弗托的联合治疗方案。虽然拉卡弗托用于纠正 p.Phe508del 突变（第 508 位苯丙氨酸缺失）并增加细胞表面定位的 CFTR 蛋白的数量，伊伐卡弗托作为 CFTR 增强剂，增加 CFTR 通道的开放概率。由于受囊性纤维化影响的主要器官是肺，通过吸入将药物直接递送到肺部具有增强 CF 治疗效果并限制对健康组织和器官的不良反应的潜力。基于我们在通过不同纳米载体吸入递药方面的广泛经验，我们选择了纳米结构化脂质载体（NLC）用于通过吸入直接将药物递送到肺部，并在体外（正常和 CF 人支气管上皮细胞）和体内（CF 双转基因同基因/同基因小鼠）测试了载药的 NLC。结果表明，设计的 NLC 表现出高药物载药量并被 CF 细胞的细胞质内化。发现载药的 NLC 能够恢复 CFTR 蛋白的表达和功能。因此，直接将脂质纳米颗粒负载的拉卡弗托和伊伐卡弗托递送到肺部，对治疗囊性纤维化的肺部表现非常有效。
