Andrade Stéphanie, Loureiro Joana A, Ramirez Santiago, Catumbela Celso S G, Soto Claudio, Morales Rodrigo, Pereira Maria Carmo
LEPABE, Department of Chemical Engineering, Faculty of Engineering, University of Porto, 4200-465 Porto, Portugal.
ALiCE-Associate Laboratory in Chemical Engineering, Faculty of Engineering, University of Porto, Rua Dr. Roberto Frias, 4200-465 Porto, Portugal.
Pharmaceuticals (Basel). 2022 Jun 18;15(6):761. doi: 10.3390/ph15060761.
Liposomes are widely used as delivery systems for therapeutic purposes. However, the toxicity associated with the multi-dose administration of these nanoparticles is not fully elucidated. Here, we evaluated the toxicity of the prolonged administration of liposomes composed of neutral or cationic phospholipids often used in drug and gene delivery. For that purpose, adult wild-type mice (C57Bl6) were randomly distributed into three groups receiving either vehicle (PBS), neutral, or cationic liposomes and subjected to repeated intravenous injections for a total of 10 doses administered over 3 weeks. Several parameters, including mortality, body weight, and glucose levels, were monitored throughout the trial. While these variables did not change in the group treated with neutral liposomes, the group treated with the positively charged liposomes displayed a mortality rate of 45% after 10 doses of administration. Additional urinalysis, blood tests, and behavioral assays to evaluate impairments of motor functions or lesions in major organs were also performed. The cationic group showed less forelimb peak force than the control group, alterations at the hematological level, and inflammatory components, unlike the neutral group. Overall, the results demonstrate that cationic liposomes are toxic for multi-dose administration, while the neutral liposomes did not induce changes associated with toxicity. Therefore, our results support the use of the well-known neutral liposomes as safe drug shuttles, even when repetitive administrations are needed.
脂质体作为治疗用途的递送系统被广泛应用。然而，与这些纳米颗粒多次给药相关的毒性尚未完全阐明。在此，我们评估了由常用于药物和基因递送的中性或阳离子磷脂组成的脂质体长期给药的毒性。为此，将成年野生型小鼠（C57Bl6）随机分为三组，分别接受载体（PBS）、中性或阳离子脂质体，并进行重复静脉注射，在3周内共注射10剂。在整个试验过程中监测了几个参数，包括死亡率、体重和血糖水平。虽然在接受中性脂质体治疗的组中这些变量没有变化，但在接受带正电荷脂质体治疗的组中，给药10剂后死亡率为45%。还进行了额外的尿液分析、血液检测以及行为分析，以评估运动功能障碍或主要器官损伤。与中性组不同，阳离子组的前肢峰值力低于对照组，血液学水平和炎症成分有改变。总体而言，结果表明阳离子脂质体多次给药有毒性，而中性脂质体不会引起与毒性相关的变化。因此，我们的结果支持即使在需要重复给药时，也可将众所周知的中性脂质体用作安全的药物载体。
