Viana Iara Maíra de Oliveira, Grenier Philippe, Defrêne Joan, Barabé Frédéric, Lima Eliana Martins, Bertrand Nicolas
Laboratory of Pharmaceutical Technology (FarmaTec), Federal University of Goiás, Goiânia, 74605-220 Goiás, Brazil.
Nanoscale. 2020 Sep 28;12(36):18875-18884. doi: 10.1039/d0nr04100a. Epub 2020 Sep 9.
Nanomedicines, including liposomes, have been used to improve the clinical efficacy and safety of drugs. In some liposomal formulations, a hydrophilic polymer coating of poly(ethylene glycol) (PEG) is used to increase the circulation time. Understanding the biological mechanisms responsible for the clearance of PEGylated and non-PEGylated nanomedicines is necessary to develop better-performing materials. The purpose of this work is to explore the role of complement in the elimination of intravenously administered liposomes (PEGylated and non-PEGylated) in mice and rats. Here, the complement cascade was depleted by intraperitoneal injections of cobra venom factor (CVF) 12 and 24 hours before the intravenous injection of radiolabeled liposomes. In both mice and rats, non-PEGylated liposomes showed faster elimination than PEGylated liposomes. At a lipid dose of 20 mg kg, the abrogation of the complement cascade (in CVF group) did not alter the circulation time of either PEGylated or non-PEGylated liposomes. In contrast, at lower doses (2 mg kg), animals treated with CVF had slightly higher levels of circulating liposomes, especially during the 24 hours pharmacokinetic studies. The complement cascade seems to govern the uptake of non-PEGylated liposomes by splenic B cells. Altogether, these results suggest that although PEGylated and non-PEGylated liposomes can activate complement, the impact of this cascade on their circulation time is minor and mostly perceivable at later phases of distribution. This work enlightens biological pathways responsible for in vivo clearance of liposomes and will help in orienting future research in elucidating the nano-bio interface.
包括脂质体在内的纳米药物已被用于提高药物的临床疗效和安全性。在一些脂质体制剂中，聚乙二醇（PEG）的亲水性聚合物涂层被用于延长循环时间。了解负责清除聚乙二醇化和非聚乙二醇化纳米药物的生物学机制对于开发性能更优的材料是必要的。这项工作的目的是探讨补体在小鼠和大鼠体内清除静脉注射的脂质体（聚乙二醇化和非聚乙二醇化）中的作用。在此，在静脉注射放射性标记脂质体前12小时和24小时腹腔注射眼镜蛇毒因子（CVF）以消耗补体级联反应。在小鼠和大鼠中，非聚乙二醇化脂质体的清除速度均比聚乙二醇化脂质体快。在脂质剂量为20 mg/kg时，补体级联反应的消除（CVF组）并未改变聚乙二醇化或非聚乙二醇化脂质体的循环时间。相比之下，在较低剂量（2 mg/kg）时，接受CVF治疗的动物循环脂质体水平略高，尤其是在24小时药代动力学研究期间。补体级联反应似乎控制着脾脏B细胞对非聚乙二醇化脂质体的摄取。总之，这些结果表明，虽然聚乙二醇化和非聚乙二醇化脂质体均可激活补体，但该级联反应对其循环时间的影响较小，且大多在分布后期才可察觉。这项工作揭示了负责脂质体体内清除的生物学途径，并将有助于指导未来阐明纳米-生物界面的研究。
