Tumor targeting using anti-her2 immunoliposomes
Tumor targeting using anti-her2 immunoliposomes
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DOI：
10.1016/s0168-3659(01)00315-7
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发表时间：
2001-07-06
影响因子：
10.8
通讯作者：
Benz, CC
中科院分区：
文献类型：
--
作者：
Park, JW;Kirpotin, DB;Benz, CC
我们已经产生了抗HER2（ErbB2）免疫脂质体（IL），其由与抗HER2单克隆抗体（MAb）片段连接的长循环脂质体组成，以向HER2过表达细胞提供靶向药物递送。使用模块化策略构建免疫脂质体，其中组件针对内化和细胞内药物递送进行优化。参数包括抗体构建体的选择、抗体密度、抗体缀合程序和脂质体构建体的选择。通过荧光显微镜、电子显微镜和荧光探针递送的定量分析确定，抗HER2免疫脂质体在体外有效结合并内化于HER2过表达细胞中。在HER2过表达细胞中通过IL递送产生的药物摄取比非靶向空间稳定脂质体高700倍。在体内，抗HER2 IL在正常成年大鼠中单次静脉给药后显示出极长的循环，作为稳定的构建体，其药代动力学与空间稳定的脂质体无法区分。重复给药显示清除率没有增加，进一步证实了IL保留了空间稳定脂质体的长循环和非免疫原性。在5种不同的HER2过表达异种移植模型中，负载多柔比星（dox）的抗HER2 IL显示出有效的抗癌活性，包括肿瘤抑制、消退和治愈（病理学完全缓解）。IL显着优于所有其他测试的治疗条件：游离dox、脂质体dox、游离MAb（曲妥珠单抗）以及dox + MAb或脂质体dox + MAb的组合。上级。例如，与非靶向脂质体相比，IL产生显著上级的抗肿瘤作用（P值为0.05）。
We have generated anti-HER2 (ErbB2) immunoliposomes ILs), consisting of long circulating liposomes linked to anti-HER2 monoclonal antibody (MAb) fragments, to provide targeted drug delivery to HER2-overexpressing cells. Immunoliposomes were constructed using a modular strategy in which components were optimized for internalization and intracellular drug delivery. Parameters included choice of antibody construct, antibody density, antibody conjugation procedure, and choice of liposome construct. Anti-HER2 immunoliposomes bound efficiently to and internalized in HER2-overexpressing cells in vitro as determined by fluorescence microscopy, electron microscopy, and quantitative analysis of fluorescent probe delivery. Delivery via ILs in HER2-overexpressing cells yielded drug uptake that was up to 700-fold greater than with non-targeted sterically stabilized liposomes. In vivo, anti-HER2 ILs showed extremely long circulation as stable constructs in normal adult rats after a single i.v. dose, with pharmacokinetics that were indistinguishable from sterically stabilized liposomes. Repeat administrations revealed no increase in clearance, further confirming that ILs retain the long circulation and non-immunogenicity of sterically stabilized liposomes. In five different HER2-overexpressing xenograft models, anti-HER2 ILs loaded with doxorubicin (dox) showed potent anticancer activity, including tumor inhibition, regressions, and cures (pathologic complete responses). ILs were significantly superior vs. all other treatment conditions tested: free dox, liposomal dox, free MAb (trastuzumab), and combinations of dox + MAb or liposomal dox + MAb. For example, ILs produced significantly superior antitumor effects vs. non-targeted liposomes (P values from