Premature Drug Release from Polyethylene Glycol (PEG)-Coated Liposomal Doxorubicin via Formation of the Membrane Attack Complex
Premature Drug Release from Polyethylene Glycol (PEG)-Coated Liposomal Doxorubicin via Formation of the Membrane Attack Complex
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DOI：
10.1021/acsnano.9b07218
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发表时间：
2020-07-28
期刊：
影响因子：
17.1
通讯作者：
Roffler, Steve R.
中科院分区：
文献类型：
--
作者：
Chen, Even;Chen, Bing-Mae;Roffler, Steve R.
抗聚乙二醇（PEG）抗体存在于许多健康个体以及接受聚乙二醇功能化药物的患者中。针对PEG包被的纳米载体的抗体可以加速它们的清除，但它们对纳米药物性质（包括纳米载体完整性）的影响尚不清楚。在这里，我们表明，抗PEG IgG和IgM抗体结合到PEG包被的脂质体阿霉素（Doxil，Doxisome，LC-101，和Lipo-Dox）的表面上的PEG分子，导致补体激活，在脂质体膜中形成膜攻击复合物（C51/-9），并从脂质体中快速释放封装的阿霉素。药物释放依赖于补体激活的经典和替代途径。在用抗PEG IgG和PEG包被的多柔比星脂质体处理的大鼠中也观察到多柔比星释放高达40%。我们的研究结果表明，抗PEG抗体可以通过激活补体破坏PEG包被的脂质体阿霉素的膜完整性，这可能会改变预先存在高水平抗PEG抗体的患者的治疗疗效和安全性。
Anti-polyethylene glycol (PEG) antibodies are present in many healthy individuals as well as in patients receiving polyethylene glycol-functionalized drugs. Antibodies against PEG-coated nanocarriers can accelerate their clearance, but their impact on nanodrug properties including nanocarrier integrity is unclear. Here, we show that anti-PEG IgG and IgM antibodies bind to PEG molecules on the surface of PEG-coated liposomal doxorubicin (Doxil, Doxisome, LC-101, and Lipo-Dox), resulting in complement activation, formation of the membrane attack complex (C51/-9) in the liposomal membrane, and rapid release of encapsulated doxorubicin from the liposomes. Drug release depended on both classical and alternative pathways of complement activation. Doxorubicin release of up to 40% was also observed in rats treated with anti-PEG IgG and PEG-coated liposomal doxorubicin. Our results demonstrate that anti-PEG antibodies can disrupt the membrane integrity of PEG-coated liposomal doxorubicin through activation of complement, which may alter therapeutic efficacy and safety in patients with high levels of pre-existing antibodies against PEG.