文献：Mannosylation of budesonide palmitate nanoprodrugs for improved macrophage targeting

作者：

Ludmila Pinheiro do Nascimento a, Nicolas Tsapis a, Franceline Reynaud a b, Didier Desmaële a, Laurence Moine a, Juliette Vergnaud a, Sonia Abreu c, Pierre Chaminade c, Elias Fattal

文献链接：https://www.sciencedirect.com/science/article/abs/pii/S0939641121003507

摘要：

In a strategy to improve macrophage targeting of glucocorticoids (GCs) for anti-inflammatory therapy, a so-called nanoprodrug of budesonide palmitate decorated by mannose moieties was designed. The synthesis of budesonide palmitate (BP) was obtained by esterification and mannosylated lipid (DSPE-PEG-Man) by reacting 1,2-Distearoyl-sn-Glycero-3-Phosphoethanolamine (DSPE)-polyethylene glycol-amine and α-D-mannopyranosylphenyl isothiocyanate (MPITC). Nanoparticles were formulated by emulsion-evaporation and different ratios of mannosylated lipid were introduced in the formulation of BP nanoprodrugs. Using up to 75% of DSPE-PEG-man (75/25) led to 200 nm particles with a polydispersity index below 0.2, a negative zeta potential ranging from −10 to −30 mV, and one-month stability at 4 °C. The encapsulation efficiency of BP approached 100% proving that the prodrug was associated with the particles, leading to a final BP loading of 50-to 60% (w/w). The lectin agglutination test confirmed the availability of mannose on the nanoprodrug surface. Nanoprodrug uptake by RAW 264.7 macrophages was observed by confocal microscopy and flow cytometry. After 24 and 48 h of incubation, a significantly greater internalization of mannosylated nanoparticles as compared to PEGylated nanoparticles was achieved. The mannose receptor-mediated uptake was confirmed by a mannan inhibition study. After LPS-induced inflammation, the anti-inflammatory effect of mannosylated nanoparticles was assessed. After 48 h of incubation, cytokines (MCP-1 and TNFα) were reduced demonstrating that the functionalization of nanoprodrugs is possible and efficient.

为了提高糖皮质激素（GC）在治疗中的巨噬细胞靶向性，设计了一种由甘露糖部分修饰的布地奈德棕榈酸酯纳米药物。

布地奈德棕榈酸酯（BP）的合成是通过1,2-二硬脂酰-sn-甘油-3-磷酸乙醇胺（DSPE）-聚乙二醇胺和α-D-吡喃甘露糖基苯基异硫氰酸酯（MPITC）的酯化和甘露糖基化脂质（DSPE-PEG-Man）反应获得的。通过乳液蒸发制备纳米颗粒，并在BP纳米药物的配方中引入不同比例的甘露糖基化脂质。

使用高达75%的DSPE PEG man（75/25）可得到多分散指数低于0.2的200 nm颗粒，负ζ电位范围为-10至-30 mV，在4°C下稳定一个月。BP的包封效率接近100%，证明前药与颗粒有关，最终BP负载量为50%至60%（w/w）。凝集素凝集试验证实了甘露糖在纳米药物表面的可用性。

通过共聚焦显微镜和流式细胞术观察RAW 264.7巨噬细胞对纳米前药的摄取。在孵育24和48小时后，与PEG化纳米颗粒相比，甘露糖基化纳米颗粒的内化明显更大。

甘露聚糖抑制研究证实了甘露糖受体介导的摄取。孵育48小时后，细胞因子（MCP-1和TNFα）减少，表明纳米药物的功能化是可能和有效的。

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