School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, 110016, China.
School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, 110016, China.
Acta Biomater. 2022 Jul 15;147:391-402. doi: 10.1016/j.actbio.2022.05.038. Epub 2022 May 26.
Direct biomimetic modification of nanoparticles (NPs) with endogenous surfactants is helpful to improve the biocompatibility of NPs and avoid damage to the physiological function of the lung. Therefore, the objective of this study is to investigate the influence of biomimetic endogenous pulmonary surfactant phospholipid modification on the in vivo fate of NPs after lung delivery. Here, two neutral phospholipids (dipalmitoylphosphatidylcholine (DPPC), dipalmitoylphosphatidylamine (DPPE)) and two negatively charged phospholipids (dipalmitoylphosphatidylglycerol (DPPG), dipalmitoylphosphatidylserine (DPPS)) were selected to modify paclitaxel (PTX)-loaded PLGA NPs with different molar ratio. DPPC, DPPE, and DPPG improved mucoadhesion, in contrast, DPPS improved the mucus permeability of the NPs. Neutral DPPC and DPPE reduced, but negatively charged DPPS and DPPG increased the uptake by alveolar macrophages, all types of phospholipid increased the uptake by lung epithelial cells and increased PTX retention in the whole lung. Whereas, DPPC, DPPE, and DPPG promoted PTX retention in bronchoalveolar lavage fluid (BALF), while DPPS promoted PTX absorption in the lung tissue. Only DPPS-PLGA (1:1) NPs remarkably increased PTX systemic exposure. A good correlation between PTX percentage in the supernatant of BALF and PTX concentration in plasma was established, implying PTX entered the system circulation mainly in molecular form. Phospholipid modification had no effect on extrapulmonary organ distribution of PTX. Taken together, our study disclosed that different phospholipid modification can endow the NPs mucoadhesive or mucus penetration and cellular uptake properties, with tunable retention in BALF and absorption in the lung tissue, providing the scientific background for translational nanocarrier design for inhalation as required. STATEMENT OF SIGNIFICANCE: Inhaled nanomedicines will inevitably interact with pulmonary surfactant and form "surfactant corona". However, the contribution of individual pulmonary surfactant phospholipid on the in vivo fate of nanomedicines is still unclear. In this regard, the most abundant pulmonary surfactant phospholipid dipalmitoylphosphatidylcholine and dipalmitoylphosphatidylamine, and dipalmitoylphosphatidylglycerol and dipalmitoylphosphatidylserine were selected to modify the paclitaxel loaded PLGA nanoparticles and the effect of these pulmonary surfactant phospholipids on their in vivo fate was investigated. It was demonstrated that different phospholipid modification can endow the nanoparticles mucoadhesive or mucus penetration properties, with tunable retention in bronchoalveolar lavage fluid, alveolar macrophages uptake and absorption in the lung tissue. The present study provided a comprehensive understanding for the role of pulmonary surfactant phospholipid on inhaled nanomedicines.
直接用内源性表面活性剂仿生修饰纳米颗粒（NPs）有助于提高 NPs 的生物相容性并避免损害肺部的生理功能。因此，本研究旨在探讨仿生内源性肺表面活性剂磷脂修饰对肺部给药后 NPs 体内命运的影响。在这里，选择了两种中性磷脂（二棕榈酰磷脂酰胆碱（DPPC）、二棕榈酰磷脂酰胺（DPPE））和两种负电荷磷脂（二棕榈酰磷脂酰甘油（DPPG）、二棕榈酰磷脂酰丝氨酸（DPPS））来修饰载紫杉醇（PTX）的 PLGA NPs，并用不同的摩尔比进行修饰。DPPC、DPPE 和 DPPG 改善了黏膜黏附性，而 DPPS 改善了 NPs 的黏液透过性。中性 DPPC 和 DPPE 减少了肺泡巨噬细胞的摄取，但带负电荷的 DPPS 和 DPPG 增加了摄取，所有类型的磷脂均增加了肺上皮细胞的摄取并增加了整个肺部的 PTX 保留。然而，DPPC、DPPE 和 DPPG 促进了支气管肺泡灌洗液（BALF）中 PTX 的保留，而 DPPS 促进了肺组织中 PTX 的吸收。只有 DPPS-PLGA（1:1）NPs 显著增加了 PTX 的全身暴露。BALF 上清液中 PTX 的百分比与血浆中 PTX 浓度之间建立了良好的相关性，这表明 PTX 主要以分子形式进入系统循环。磷脂修饰对 PTX 的肺外器官分布没有影响。总之，我们的研究揭示了不同的磷脂修饰可以赋予 NPs 黏膜黏附性或黏液透过性和细胞摄取特性，并可调节 BALF 中的保留和肺组织中的吸收，为按需设计吸入用纳米载体提供了科学依据。意义声明：吸入性纳米药物不可避免地会与肺表面活性剂相互作用并形成“表面活性剂冠”。然而，单个肺表面活性剂磷脂对纳米药物体内命运的贡献仍不清楚。在这方面，选择了最丰富的肺表面活性剂磷脂二棕榈酰磷脂酰胆碱和二棕榈酰磷脂酰胺，以及二棕榈酰磷脂酰甘油和二棕榈酰磷脂酰丝氨酸来修饰载紫杉醇的 PLGA 纳米颗粒，并研究了这些肺表面活性剂磷脂对其体内命运的影响。结果表明，不同的磷脂修饰可以赋予纳米粒子黏膜黏附性或黏液透过性，可调节支气管肺泡灌洗液中的保留、肺泡巨噬细胞摄取和肺组织吸收。本研究为肺表面活性剂磷脂对吸入性纳米药物的作用提供了全面的认识。
