College of Pharmacy, Chungbuk National University, Cheongju, 28160, Republic of Korea.
School of Pharmacy, Institute of New Drug Development, and Respiratory Drug Development Research Institute, Jeonbuk National University, Jeonju, Republic of Korea.
Int J Nanomedicine. 2024 Sep 7;19:9195-9211. doi: 10.2147/IJN.S474287. eCollection 2024.
Effective mucosal delivery of drugs continues to pose a significant challenge owing to the formidable barrier presented by the respiratory tract mucus, which efficiently traps and clears foreign particulates. The surface characteristics of micelles dictate their ability to penetrate the respiratory tract mucus. In this study, polymeric micelles loaded with insulin (INS) were modified using mucus-penetrative polymers.
We prepared and compared polyethylene glycol (PEG)-coated micelles with micelles where cell-penetrating peptide (CPP) is conjugated to PEG. Systematic investigations of the physicochemical and aerosolization properties, performance, in vitro release, mucus and cell penetration, lung function, and pharmacokinetics/pharmacodynamics (PK/PD) of polymeric micelles were performed to evaluate their interaction with the respiratory tract.
The nano-micelles, with a particle size of <100 nm, exhibited a sustained-release profile. Interestingly, PEG-coated micelles exhibited higher diffusion and deeper penetration across the mucus layer. In addition, CPP-modified micelles showed enhanced in vitro cell penetration. Finally, in the PK/PD studies, the micellar solution demonstrated higher maximum concentration (C) and AUC values than subcutaneously administered INS solution, along with a sustained blood glucose-lowering effect that lasted for more than 8 h.
This study proposes the use of mucus-penetrating micelle formulations as prospective inhalation nano-carriers capable of efficiently transporting peptides to the respiratory tract.
由于呼吸道黏液构成了难以逾越的屏障，其能有效捕获并清除外来颗粒，因此，药物的有效黏膜递送仍然是一个重大挑战。胶束的表面特性决定了其穿透呼吸道黏液的能力。在这项研究中，载胰岛素（INS）的聚合物胶束经过了穿透黏液聚合物的修饰。
我们制备并比较了聚乙二醇（PEG）涂层胶束与将细胞穿透肽（CPP）连接到 PEG 的胶束。系统性地研究了物理化学和雾化特性、性能、体外释放、黏液和细胞穿透、肺功能以及聚合物胶束的药代动力学/药效学（PK/PD），以评估它们与呼吸道的相互作用。
纳米胶束的粒径<100nm，表现出持续释放的特征。有趣的是，PEG 涂层胶束在黏液层中的扩散和穿透更深。此外，CPP 修饰的胶束显示出增强的体外细胞穿透性。最后，在 PK/PD 研究中，与皮下给予的 INS 溶液相比，胶束溶液表现出更高的最大浓度（C）和 AUC 值，以及持续超过 8 小时的降血糖作用。
本研究提出使用穿透黏液的胶束制剂作为有前途的吸入纳米载体，能够将肽有效递送到呼吸道。
