Department of Bioscience and Biotechnology, Konkuk University, Seoul 143-701, Republic of Korea.
College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Republic of Korea.
Int J Pharm. 2024 Sep 5;662:124540. doi: 10.1016/j.ijpharm.2024.124540. Epub 2024 Jul 27.
This study compared the effects of polyethylene glycol (PEG) shielding and mannose-conjugated ligands density on lipid nanoparticles (LNPs) for intracellular uptake to macrophages in vitro and accumulation in spleens in vivo. Fabricated phosphatidyl serine-incorporated LNPs (sLNPs) was physically decorated with mannose-conjugated DSPE-PEG (DPM) at different DPM/LNP molar ratios achieving the DPM density from 0 to 0.6 PEGs/nm. We demonstrated that low PEG shielding sLNPs with mannose ligands (sLNP-DPMs) displayed superior uptake to macrophages (RAW 264.7 cells) compared with high PEG shielding sLNP-DPMs in vitro. However, high PEG shielding sLNP-DPMs showed significant spleen accumulation compared with low PEG shielding sLNP-DPMs in vivo after intravenous injection. In particular, high PEG shielding sLNPs coated with DSPE-methoxyPEG (DP) and DPM mixture at DP/DPM molar ratios of 5/5 exhibited greater accumulation in red pulp of spleens than naked sLNPs by 2.7-folds in vivo. These results suggested that the optimal PEG shielding and mannose densities per a particle might be different between in vitro cellular uptake to macrophages and in vivo spleen accumulation after systemic administration. Taken together, precision-tailored LNP-surface modifications achieved through optimization of PEG shielding and mannose density can greatly enhance accumulation of LNPs in red pulp of spleens, which could be applied for the delivery of nucleic acid-based drugs and vaccines to spleens in vivo.
本研究比较了聚乙二醇（PEG）屏蔽和甘露糖偶联配体密度对体外细胞内摄取巨噬细胞和体内脾脏蓄积的脂质纳米颗粒（LNPs）的影响。制备了含有磷脂酰丝氨酸的 LNPs（sLNPs），并用不同 DPM/LNP 摩尔比的甘露糖偶联 DSPE-PEG（DPM）物理修饰，实现了 DPM 密度从 0 到 0.6 PEGs/nm。我们证明，与高 PEG 屏蔽 sLNP-DPMs 相比，具有甘露糖配体的低 PEG 屏蔽 sLNPs（sLNP-DPMs）在体外对巨噬细胞（RAW 264.7 细胞）的摄取具有优势。然而，静脉注射后，高 PEG 屏蔽 sLNP-DPMs 在体内比低 PEG 屏蔽 sLNP-DPMs 表现出明显的脾脏蓄积。特别是，在 DP/DPM 摩尔比为 5/5 的 DP 和 DPM 混合物涂覆的高 PEG 屏蔽 sLNPs 比裸 sLNPs 在体内表现出 2.7 倍的更高脾脏红髓蓄积。这些结果表明，在体外细胞摄取巨噬细胞和体内系统给药后脾脏蓄积之间，每个颗粒的最佳 PEG 屏蔽和甘露糖密度可能不同。总之，通过优化 PEG 屏蔽和甘露糖密度实现的精确定制 LNP 表面修饰可以大大增强 LNPs 在脾脏红髓中的蓄积，这可应用于体内将核酸药物和疫苗递送至脾脏。
