State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.
Beijing Key Laboratory of Drug Delivery Technology and Novel Formulation, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.
Molecules. 2022 Jul 9;27(14):4408. doi: 10.3390/molecules27144408.
Surface charge polarity and density influence the immune clearance and cellular uptake of intravenously administered lipid nanoparticles (LNPs), thus determining the efficiency of their delivery to the target. Here, we modified the surface charge with ascorbyl palmitate (AsP) used as a negatively charged lipid. AsP-PC-LNPs were prepared by dispersion and ultrasonication of AsP and phosphatidylcholine (PC) composite films at various ratios. AsP inserted into the PC film with its polar head outward. The pKa for AsP was 4.34, and its ion form conferred the LNPs with negative surface charge. Zeta potentials were correlated with the amount and distribution of AsP on the LNPs surface. DSC, Raman and FTIR spectra, and molecular dynamics simulations disclosed that AsP distributed homogeneously in PC at 1−8% (w/w), and there were strong hydrogen bonds between the polar heads of AsP and PC (PO2−), which favored LNPs’ stability. But at AsP:PC > 8% (w/w), the excessive AsP changed the interaction modes between AsP and PC. The AsP−PC composite films became inhomogeneous, and their phase transition behaviors and Raman and FTIR spectra were altered. Our results clarified the mechanism of surface charge modification by AsP and provided a rational use of AsP as a charged lipid to modify LNP surface properties in targeted drug delivery systems. Furthermore, AsP−PC composites were used as phospholipid-based biological membranes to prepare paclitaxel-loaded LNPs, which had stable surface negative charge, better tumor targeting and tumor inhibitory effects.
表面电荷极性和密度会影响静脉内给予的脂质纳米粒（LNPs）的免疫清除和细胞摄取，从而决定其递送至靶标的效率。在这里，我们用抗坏血酸棕榈酸酯（AsP）作为带负电荷的脂质来修饰表面电荷。通过在不同比例下将 AsP 和磷脂酰胆碱（PC）复合膜分散和超声处理来制备 AsP-PC-LNPs。AsP 的极性头向外插入 PC 膜中。AsP 的 pKa 为 4.34，其离子形式赋予 LNPs 负表面电荷。Zeta 电位与 LNPs 表面上 AsP 的数量和分布相关。差示扫描量热法（DSC）、拉曼和傅里叶变换红外（FTIR）光谱以及分子动力学模拟表明，AsP 以 1-8%（w/w）的比例均匀分布在 PC 中，AsP 的极性头与 PC（PO2-）之间存在强氢键，这有利于 LNPs 的稳定性。但是当 AsP:PC > 8%（w/w）时，过多的 AsP 改变了 AsP 和 PC 之间的相互作用模式。AsP-PC 复合膜变得不均匀，其相变行为和拉曼和 FTIR 光谱发生改变。我们的结果阐明了 AsP 修饰表面电荷的机制，并为合理使用 AsP 作为带电脂质来修饰靶向药物递送系统中的 LNP 表面性质提供了依据。此外，AsP-PC 复合材料被用作基于磷脂的生物膜来制备负载紫杉醇的 LNPs，其具有稳定的表面负电荷、更好的肿瘤靶向性和肿瘤抑制作用。
