School of Pharmacy, Xi'an Jiaotong University, Xi'an, China.
Department of Pharmacy, Xi'an Medical College, Xi'an, China.
Drug Dev Ind Pharm. 2021 Feb;47(2):337-346. doi: 10.1080/03639045.2021.1879837. Epub 2021 Feb 4.
This study aims to investigate the potential of DSPE-PEG polymers (DSPE-PEG-OH and DSPE-PEG-SH) on improving absorption of poorly absorbable macromolecules intrapulmonary administration and underlying mechanism.
pulmonary absorption experiments were performed to investigate the absorption of model compounds after intrapulmonary administration to rats. The local membrane damage induced by these DSPE-PEG polymers were evaluated based on morphological observation of lung tissues and measurement of biological toxic markers in bronchoalveolar lavage fluid (BALF) postintrapulmonary delivery of DSPE-PEG polymers to rats. The underlying enhancement mechanism of these polymers was explored by investigating their effects on the pulmonary membrane fluidity and gene expression of tight junction associated proteins with fluorescence polarization and western blotting, respectively.
Intrapulmonary delivery of these DSPE-PEG polymers significantly enhanced absorptions of poorly absorbed model drugs and did not induce serious damage to the pulmonary membranes of rats. Mechanistic studies demonstrated unaffected pulmonary membrane fluidity and up-regulated expression levels of tight junction-associated proteins by DSPE-PEG polymers, thus indicating that paracellular pathways might be included in the underlying mechanisms by which DSPE-PEG polymers exerted their enhancing actions on drug absorption.
These findings suggested that these DSPE-PEG polymers are potential for promoting absorptions of poorly absorbable macromolecules with no evidence of damage to the local pulmonary membranes of rats.Novelty statementIn this study, DSPE-PEG-OH and DSPE-PEG-SH polymers, two DSPE-PEG2000 conjugates with different terminal groups demonstrated significant promoting effects on the absorption of poorly absorbed macromolecular drugs after intrapulmonary delivery to rats, and did not induce serious damage to the pulmonary membranes of rats. These DSPE-PEG polymers could statistically downregulate expression levels of tight junction-associated proteins (ZO-1 and occludin), indicating the underlying mechanism by which these polymers exerted their absorption enhancing actions through pulmonary epithelial paracellular pathways. Thus, this study exhibited prospective potential of these DSPE-PEG polymers in developing into dosage forms with the aim to improve the poor bioavailability of some poorly absorbed macromolecular drugs.
本研究旨在探讨 DSPE-PEG 聚合物（DSPE-PEG-OH 和 DSPE-PEG-SH）在提高肺部给药时吸收难吸收大分子的潜力及其潜在机制。
通过肺部吸收实验，研究了模型化合物在肺部给药后吸收情况。通过观察肺部组织的形态学变化和测量支气管肺泡灌洗液（BALF）中的生物毒性标志物，评估这些 DSPE-PEG 聚合物对肺部给药后局部膜损伤的影响。通过荧光偏振和 Western 印迹法分别研究这些聚合物对肺膜流动性和紧密连接相关蛋白基因表达的影响，探讨这些聚合物的潜在增强机制。
肺部给予这些 DSPE-PEG 聚合物可显著增强难吸收模型药物的吸收，且不会对大鼠肺部膜造成严重损伤。机制研究表明，DSPE-PEG 聚合物不影响肺膜流动性，且上调紧密连接相关蛋白的表达水平，表明细胞旁途径可能是 DSPE-PEG 聚合物增强药物吸收的潜在机制之一。
这些发现表明，这些 DSPE-PEG 聚合物可能具有促进难吸收大分子吸收的潜力，且无证据表明它们会对大鼠肺部局部膜造成损伤。
在这项研究中，两种不同末端基团的 DSPE-PEG2000 缀合物 DSPE-PEG-OH 和 DSPE-PEG-SH 聚合物在肺部给药后显著促进了难吸收大分子药物的吸收，且未对大鼠肺部膜造成严重损伤。这些 DSPE-PEG 聚合物可统计学地下调紧密连接相关蛋白（ZO-1 和 occludin）的表达水平，表明这些聚合物通过肺上皮细胞旁途径发挥吸收增强作用的潜在机制。因此，这项研究展示了这些 DSPE-PEG 聚合物在开发旨在提高某些难吸收大分子药物生物利用度的新剂型方面的潜在前景。
