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Immunological response to nitroglycerin-loaded shear-responsive liposomes in vitro and in vivo
Journal of Controlled Release ( IF 10.8 ) Pub Date : 2017-08-10 , DOI: 10.1016/j.jconrel.2017.08.010
Marzia Buscema , Sofiya Matviykiv , Tamás Mészáros , Gabriela Gerganova , Andreas Weinberger , Ute Mettal , Dennis Mueller , Frederik Neuhaus , Etienne Stalder , Takashi Ishikawa , Rudolf Urbanics , Till Saxer , Thomas Pfohl , János Szebeni , Andreas Zumbuehl , Bert Müller

Liposomes formulated from the 1,3-diamidophospholipid Pad-PC-Pad are shear-responsive and thus promising nano-containers to specifically release a vasodilator at stenotic arteries. The recommended preclinical safety tests for therapeutic liposomes of nanometer size include the in vitro assessment of complement activation and the evaluation of the associated risk of complement activation-related pseudo-allergy (CARPA) in vivo. For this reason, we measured complement activation by Pad-PC-Pad formulations in human and porcine sera, along with the nanopharmaceutical-mediated cardiopulmonary responses in pigs. The evaluated formulations comprised of Pad-PC-Pad liposomes, with and without polyethylene glycol on the surface of the liposomes, and nitroglycerin as a model vasodilator. The nitroglycerin incorporation efficiency ranged from 25% to 50%. In human sera, liposome formulations with 20 mg/mL phospholipid gave rise to complement activation, mainly via the alternative pathway, as reflected by the rises in SC5b-9 and Bb protein complex concentrations. Formulations having a factor of ten lower phospholipid content did not result in measurable complement activation. The weak complement activation induced by Pad-PC-Pad liposomal formulations was confirmed by the results obtained by performing an in vivo study in a porcine model, where hemodynamic parameters were monitored continuously. Our study suggests that, compared to FDA-approved liposomal drugs, Pad-PC-Pad exhibits less or similar risks of CARPA.



中文翻译:

在体外体内对硝酸甘油负载的剪切响应脂质体的免疫学反应

由1,3-二氨基磷酸脂Pad-PC-Pad配制的脂质体具有剪切响应能力,因此有望在纳米容器中特异性释放血管扩张剂。推荐的纳米级治疗性脂质体的临床前安全性测试包括体内补体激活评估和体内补体激活相关假性变态反应(CARPA)相关风险的评估。因此,我们在人和猪血清中测量了Pad-PC-Pad制剂的补体激活,以及猪中纳米药物介导的心肺反应。所评估的制剂包括Pad-PC-Pad脂质体,在脂质体表面上有和没有聚乙二醇,以及硝化甘油作为模型血管扩张剂。硝酸甘油的掺入效率为25%至50%。在人血清中,含20 mg / mL磷脂的脂质体制剂主要通过以下途径引起补体激活:通过SC5b-9和Bb蛋白复合物浓度的升高反映出了另一种途径。磷脂含量降低十倍的制剂未导致可测量的补体活化。Pad-PC-Pad脂质体制剂诱导的弱补体激活通过在猪模型中进行体内研究而获得的结果得到证实,该模型在猪模型中连续监测血流动力学参数。我们的研究表明,与FDA批准的脂质体药物相比,Pad-PC-Pad表现出更少或类似的CARPA风险。

更新日期:2017-08-10
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