School of Pharmacy, Kitasato University, Shirokane 5-9-1, Minato-ku, Tokyo 108-8641, Japan.
Scientific/Semiconductor Product R&D Center, HORIBA, Ltd., Kanda Awaji-cho 2-6, Chiyoda-ku, Tokyo 101-0063, Japan.
Mol Pharm. 2022 Jan 3;19(1):91-99. doi: 10.1021/acs.molpharmaceut.1c00645. Epub 2021 Dec 16.
Phosphatidylserine (PS) is a unique lipid that is recognized by the endogenetic receptor, T-cell immunoglobulin mucin protein 4 (Tim4), and PS-containing liposomes have potential use in therapeutic applications. We prepared PS-containing liposomes of various lipid compositions and examined how lipid membrane fluidity affects PS recognition by Tim4 and the resulting endocytosis efficiency into Hela cells. Surface plasmon resonance and laurdan studies showed that increasing lipid membrane fluidity increased the stability of the PS-Tim4 interaction but hampered the entry of liposomes into cells. These results show that endocytosis efficiency is determined by balancing opposing forces induced by membrane fluidity. We found that inclusion of the zwitterionic helper lipid, 1,2-dipalmitoyl--glycero-3-phosphocholine, into liposomes ensured efficient cellular internalization because the presence of this lipid provides an ideal balance of lipid fluidity and Tim4 affinity. The results showed that PS recognition by Tim4 and the resulting endocytosis efficiency can be maximized by modulating the membrane fluidity of liposomes by selecting a zwitterionic helper lipid. This study improves our understanding of how to rationally optimize nanotechnology for targeted drug delivery.
磷脂酰丝氨酸（PS）是一种独特的脂质，可被内源性受体 T 细胞免疫球蛋白粘蛋白蛋白 4（Tim4）识别，含有 PS 的脂质体在治疗应用中有潜在用途。我们制备了具有各种脂质组成的 PS 脂质体，并研究了脂质膜流动性如何影响 Tim4 对 PS 的识别以及随后进入 Hela 细胞的内吞效率。表面等离子体共振和 laurdan 研究表明，增加脂质膜流动性会增加 PS-Tim4 相互作用的稳定性，但阻碍了脂质体进入细胞。这些结果表明，内吞效率是通过平衡由膜流动性引起的相反力来决定的。我们发现，将两性离子辅助脂质 1,2-二棕榈酰基-甘油-3-磷酸胆碱纳入脂质体可确保有效的细胞内化，因为这种脂质的存在提供了脂质流动性和 Tim4 亲和力的理想平衡。结果表明，通过选择两性离子辅助脂质来调节脂质体的膜流动性，可以最大程度地提高 Tim4 对 PS 的识别和随后的内吞效率。这项研究提高了我们对如何通过选择两性离子辅助脂质来调节脂质体的膜流动性，从而最大程度地提高 Tim4 对 PS 的识别和随后的内吞效率。这项研究提高了我们对如何通过选择两性离子辅助脂质来调节脂质体的膜流动性，从而理性优化靶向药物递送纳米技术的理解。
