巨噬细胞是多功能的先天免疫细胞,在稳态中起着不可或缺的作用。组织修复,和免疫调节。然而,巨噬细胞的异常激活与各种人类疾病的发病机理有关,使它们成为潜在的治疗目标。通过模式识别和清道夫受体的表达,巨噬细胞表现出病原体和凋亡细胞的选择性摄取。因此,模拟致病或凋亡信号的药物载体的利用显示了靶向递送至巨噬细胞的潜力。在这项研究中,通过实验设计(DoE)策略和试错法(TaE)方法,开发了一系列甘露糖基化或/和磷脂酰丝氨酸(PS)递呈脂质体靶向巨噬细胞.基于体外对RAW264.7和THP-1的细胞摄取和细胞毒性评估的结果,脂质体制剂的最佳摩尔比为DOPC:DSPS:Chol:PEG-PE=20:60:20:2。体内分布结果表明,在DSS诱导的结肠炎模型和II型胶原诱导的类风湿性关节炎模型中,PS呈递脂质体(PS-Lipo)在肠道和爪子中的蓄积率最高,这对巨噬细胞靶向治疗具有有希望的潜力,因为巨噬细胞在炎症部位丰富,并有助于相应疾病的进展。心脏等器官,肝脏,脾,脾肺,当暴露于PC呈递脂质体(PC-Lipo)或PS-Lipo时,肾脏没有表现出组织学改变,例如炎症或坏死。此外,脂质体具有血液生物相容性,对肝脏或肾脏的循环没有毒性,并且不会引起动物的代谢损伤。因此,精心设计的PS-Lipo显示出最有潜力的巨噬细胞靶向治疗.
Macrophages are multifunctional innate immune cells that play indispensable roles in homeostasis, tissue repair, and immune regulation. However, dysregulated activation of macrophages is implicated in the pathogenesis of various human disorders, making them a potential target for treatment. Through the expression of pattern recognition and scavenger receptors, macrophages exhibit selective uptake of pathogens and apoptotic cells. Consequently, the utilization of drug carriers that mimic pathogenic or apoptotic signals shows potential for targeted delivery to macrophages. In this study, a series of mannosylated or/and phosphatidylserine (PS) -presenting liposomes were developed to target macrophages via the design of experiment (DoE) strategy and the trial-and-error (TaE) approach. The optimal molar ratio for the liposome formulation was DOPC: DSPS: Chol: PEG-PE = 20:60:20:2 based on the results of cellular uptake and cytotoxicity evaluation on RAW 264.7 and THP-1 in vitro. Results from in vivo distribution showed that, in the DSS-induced colitis model and collagen II-induced rheumatoid arthritis model, PS-presenting liposomes (PS-Lipo) showed the highest accumulation in intestine and paws respectively, which holds promising potential for macrophage target therapy since macrophages are abundant at inflammatory sites and contribute to the progression of corresponding diseases. Organs such as the heart, liver, spleen, lung, and kidney did not exhibit histological alterations such as inflammation or necrosis when exposed to PC-presenting liposomes (PC-Lipo) or PS-Lipo. In addition, liposomes demonstrated hemobiocompatibility and no toxicity to liver or kidney for circulation and did not induce metabolic injury in the animals. Thus, the well-designed PS-Lipo demonstrated the most potential for macrophage target therapy.