Li Ziling, Lei Huiling, Hu Jiannan, Zhou Tong, Yuan Shuaiqi, Ma Xinyue, Zhu Yunfei, Liu Chao, Wang Decai, Wu Yuzhou, Xu Shuyun
Department of Respiratory and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei Province, China.
Key Laboratory of Respiratory Diseases of National Health Commission, Tongji Hospital, Tongji Medical College, Huazhong University of Sciences and Technology, Wuhan, 430030, Hubei Province, China.
Mater Today Bio. 2025 Feb 18;31:101590. doi: 10.1016/j.mtbio.2025.101590. eCollection 2025 Apr.
The pneumonia induced by carbapenem resistant (CRKP) has high morbidity and mortality. Among the antibiotics currently available, polymyxin B (PMB) is considered to be the last line of defense. Routine intravenous administration of PMB has many problems, such as severe neurotoxicity and nephrotoxicity. In this study, a novel inhaled PMB-loaded albumin nanoparticles (PEG-pHSA@PMB) capable of penetrating airway mucus and responding to the infection microenvironment is constructed. An acid-responsive functional molecule (PEBA) and NH-PEG-SH are linked to the surface of human serum albumin (HSA) via the conjugation reaction. Subsequently, PMB is loaded through electrostatic interactions to yield PEG-pHSA@PMB. The sulfhydryl groups of PEG-pHSA@PMB interact with mucins to help penetrate mucus after inhaled. In an acidic environment, the protonation of the tertiary amino groups within PEG-pHSA@PMB causes the charge alteration, which leads to the release of PMB. It demonstrated excellent mucus permeability, potent bactericidal activity, and superior bacteriostatic effects compared to sole PMB. Inhalation of PEG-pHSA@PMB significantly reduced the bacterial load in the lungs of mice with CRKP pneumonia, alleviating inflammatory response. Moreover, PEG-pHSA@PMB exhibited good cytocompatibility and biosafety. The novel strategy of the inhalation drug delivery system is promising for the treatment of pneumonia caused by drug-resistant bacteria.
碳青霉烯耐药肺炎克雷伯菌（CRKP）引起的肺炎具有较高的发病率和死亡率。在目前可用的抗生素中，多粘菌素B（PMB）被认为是最后一道防线。PMB常规静脉给药存在许多问题，如严重的神经毒性和肾毒性。在本研究中，构建了一种新型的可吸入载有PMB的白蛋白纳米粒（PEG-pHSA@PMB），其能够穿透气道黏液并对感染微环境作出响应。通过偶联反应将酸响应功能分子（PEBA）和NH-PEG-SH连接到人血清白蛋白（HSA）表面。随后，通过静电相互作用负载PMB以得到PEG-pHSA@PMB。PEG-pHSA@PMB的巯基与黏蛋白相互作用，有助于吸入后穿透黏液。在酸性环境中，PEG-pHSA@PMB内叔氨基的质子化导致电荷改变，从而使PMB释放。与单独的PMB相比，它表现出优异的黏液渗透性、强大的杀菌活性和卓越的抑菌效果。吸入PEG-pHSA@PMB显著降低了CRKP肺炎小鼠肺部的细菌载量，减轻了炎症反应。此外，PEG-pHSA@PMB表现出良好的细胞相容性和生物安全性。吸入给药系统的新策略在治疗耐药菌引起的肺炎方面具有广阔前景。
