Moein Moghimi S, Hamad Islam, Bünger Rolf, Andresen Thomas L, Jørgensen Kent, Hunter A Christy, Baranji Lajos, Rosivall Laszlo, Szebeni Janos
Molecular Targeting and Polymer Toxicology, School of Pharmacy, University of Brighton, Brighton, UK.
J Liposome Res. 2006;16(3):167-74. doi: 10.1080/08982100600848801.
Intravenously infused liposomes may induce cardiopulmonary distress in some human subjects, which is a manifestation of "complement activation-related pseudoallergy." We have now examined liposome-mediated complement activation in human sera with elevated lipoprotein (LDL and HDL) levels, since abnormal or racial differences in serum lipid profiles seem to modulate the extent of complement activation and associated adverse responses. In accordance with our earlier observations, cholesterol-rich (45 mol% cholesterol) liposomes activated human complement, as reflected by a significant rise in serum level of S-protein-bound form of the terminal complex (SC5b-9). However, liposome-induced rise of SC5b-9 was significantly suppressed when serum HDL cholesterol levels increased by 30%. Increase of serum LDL to levels similar to that observed in heterozygous familial hypercholesterolemia also suppressed liposome-mediated SC5b-9 generation considerably. While intravenous injection of cholesterol-rich liposomes into pigs was associated with an immediate circulatory collapse, the drop in systemic arterial pressure following injection of liposomes preincubated with human lipoproteins was slow and extended. Therefore, surface-associated lipoprotein particles (or apolipoproteins) seem to lessen liposome-induced adverse haemodynamic changes, possibly as a consequence of suppressed complement activation in vivo. PEGylated liposomes were also capable of activating the human complement system, and the presence of surface projected methoxypoly(ethylene glycol) chains did not interfere with generation of C3 opsonic fragments. We also show that poly(ethylene glycol) is not responsible for PEGylated liposome-mediated complement activation. The net anionic charge on the phosphate moiety of the phospholipid-mPEG conjugate seemed to play a critical role in activation of both the classical and alternative pathways of the complement system.
静脉注射脂质体可能会在一些人体受试者中诱发心肺窘迫，这是“补体激活相关假过敏”的一种表现。由于血清脂质谱的异常或种族差异似乎会调节补体激活的程度及相关不良反应，我们现在研究了脂蛋白（低密度脂蛋白和高密度脂蛋白）水平升高的人血清中脂质体介导的补体激活情况。与我们早期的观察结果一致，富含胆固醇（45摩尔%胆固醇）的脂质体激活了人补体，这可通过末端复合物（SC5b-9）的S蛋白结合形式的血清水平显著升高反映出来。然而，当血清高密度脂蛋白胆固醇水平升高30%时，脂质体诱导的SC5b-9升高被显著抑制。将血清低密度脂蛋白增加到杂合子家族性高胆固醇血症中观察到的类似水平，也相当程度地抑制了脂质体介导的SC5b-9生成。虽然向猪静脉注射富含胆固醇的脂质体会导致立即循环衰竭，但注射与人脂蛋白预孵育的脂质体后，体循环动脉压的下降缓慢且持续时间长。因此，表面相关的脂蛋白颗粒（或载脂蛋白）似乎减轻了脂质体诱导的不良血液动力学变化，这可能是体内补体激活受到抑制的结果。聚乙二醇化脂质体也能够激活人补体系统，并且表面突出的甲氧基聚（乙二醇）链的存在并不干扰C3调理片段的生成。我们还表明，聚（乙二醇）与聚乙二醇化脂质体介导的补体激活无关。磷脂 - mPEG缀合物磷酸部分上的净阴离子电荷似乎在补体系统经典途径和替代途径的激活中都起关键作用。
