Department of Molecular Biology and Human Genetics, Tzu-Chi University, Hualien 970, Taiwan.
Cells. 2024 Oct 27;13(21):1778. doi: 10.3390/cells13211778.
To minimize off-target adverse effects and improve drug efficacy, various tissue-specific drug delivery systems have been developed. However, even in diseased organs, both normal and stressed, dying cells coexist, and a targeted delivery system specifically for dying cells has yet to be explored to mitigate off-target effects within the same organ. This study aimed to establish such a system. By examining the surfaces of dying cells in vitro, we identified P-selectin glycoprotein ligand-1 (PSGL-1) as a universal marker for dying cells, positioning it as a potential target for selective drug delivery. We demonstrated that liposomes conjugated with the PSGL-1 binding protein P-selectin had significantly greater binding efficiency to dying cells compared to control proteins such as E-selectin, L-selectin, galectin-1, and C-type lectin-like receptor 2. Using thioacetamide (TAA) to induce hepatitis and hepatocyte damage in mice, we assessed the effectiveness of our P-selectin-based delivery system. In vivo, P-selectin-conjugated liposomes effectively delivered fluorescent dye and the apoptosis inhibitor z-DEVD to TAA-damaged livers in wild-type mice, but not in PSGL-1 knockout mice. In TAA-treated wild-type mice, unconjugated liposomes required a 100-fold higher z-DEVD dose compared to P-selectin-conjugated liposomes to achieve a comparable, albeit less effective, therapeutic outcome in lowering plasma alanine transaminase levels and alleviating thrombocytopenia. This emphasizes that P-selectin conjugation enhances drug delivery efficiency by approximately 100-fold in mice. These results suggest that P-selectin-based liposomes could be a promising strategy for targeted drug delivery, enabling both diagnosis and treatment by specifically delivering cell-labeling agents and rescue agents to dying cells via the P-selectin-PSGL-1 axis at the individual cell level.
为了最大限度地减少脱靶不良反应并提高药物疗效，已经开发了各种组织特异性药物递送系统。然而，即使在患病器官中，正常细胞和应激细胞、死亡细胞也同时存在，因此，仍需要探索一种针对死亡细胞的靶向药物递送系统，以减轻同一器官中的脱靶效应。本研究旨在建立这样一种系统。通过在体外检查死亡细胞的表面，我们确定 P-选择素糖蛋白配体-1（PSGL-1）是死亡细胞的通用标志物，将其作为选择性药物递送的潜在靶点。我们证明，与对照蛋白（如 E-选择素、L-选择素、半乳糖凝集素-1 和 C 型凝集素样受体 2）相比，与 PSGL-1 结合蛋白 P-选择素结合的脂质体对死亡细胞的结合效率显著更高。我们使用硫代乙酰胺（TAA）在小鼠中诱导肝炎和肝细胞损伤，评估了我们基于 P-选择素的递药系统的有效性。在体内，P-选择素缀合的脂质体在野生型小鼠的 TAA 损伤肝脏中有效地递送荧光染料和凋亡抑制剂 z-DEVD，但在 PSGL-1 敲除小鼠中则没有。在 TAA 处理的野生型小鼠中，与 P-选择素缀合的脂质体相比，未缀合的脂质体需要高 100 倍的 z-DEVD 剂量才能达到类似但效果较差的治疗效果，即降低血浆丙氨酸转氨酶水平和缓解血小板减少症。这表明 P-选择素缀合在小鼠中使药物递送效率提高了约 100 倍。这些结果表明，基于 P-选择素的脂质体可能是一种有前途的靶向药物递送策略，通过 P-选择素-PSGL-1 轴在单个细胞水平上特异性地向死亡细胞递送细胞标记剂和挽救剂，从而实现诊断和治疗。
