Epidermal growth factor receptor-targeted immunoliposomes significantly enhance the efficacy of multiple anticancer drugs in vivo
Epidermal growth factor receptor-targeted immunoliposomes significantly enhance the efficacy of multiple anticancer drugs in vivo
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DOI：
10.1158/0008-5472.can-05-1093
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发表时间：
2005-12-15
期刊：
影响因子：
11.2
通讯作者：
Park, JW
中科院分区：
文献类型：
--
作者：
Mamot, C;Drummond, DC;Park, JW
我们先前报道了以表皮生长因子受体(EGFR)为靶点的免疫脂质体的发展，它结合并内化在过表达EGFR和/或突变的EGFR变异体III(EGFRvIII)的肿瘤细胞中，使有效的抗癌药物在体外能够在细胞内传递。我们现在描述了在EGFR过表达的肿瘤模型中，这种方法用于多种抗癌药物输送的体内概念验证。将西妥昔单抗(IMC-C225)的Fab‘片段与含有探针和/或抗癌药物的脂质体共价连接，以模块化方式构建抗EGFR免疫脂质体。药代动力学和生物分布研究证实，无论靶向配体是否存在，循环时间长(t(1/2)=21小时)和在肿瘤中的有效蓄积(高达15%ID/g)。尽管在EGFR过度表达的肿瘤中，抗EGFR免疫脂质体和非靶向脂质体的总蓄积量是相似的，但只有免疫脂质体广泛地内化在肿瘤细胞内(92%的分析细胞与非靶向脂质体的5%)，这表明在细胞水平上的递送机制不同。对EGFR和/或EGFRvIII过表达的一系列异种移植模型的体内治疗研究表明，免疫脂质体给药具有优越性，包括阿霉素、表阿霉素和长春瑞滨。对于这些药物中的每一种，抗EGFR免疫脂质体都显示出显著的抗肿瘤效果，并且显著优于所有其他治疗方法，包括相应的游离或脂质体药物(P<；0.001-0.003)。我们的结论是，抗EGFR免疫脂质体为抗癌化合物提供了有效和靶向的药物传递，并可能为过度表达EGFR的肿瘤提供一种有用的新的治疗方法。
We previously reported the development of epidermal growth factor receptor (EGFR)-targeted immunoliposomes that bind and internalize in tumor cells which overexpress EGFR and/or mutant EGFR variant III (EGFRvIII), enabling intracellular delivery of potent anticancer agents in vitro. We now describe in vivo proof-of-concept for this approach for the delivery of multiple anticancer drugs in EGFR-overexpressing tumor models. Anti-EGFR immunoliposomes were constructed modularly with Fab'fragments of cetuximab (IMC-C225), covalently linked to liposomes containing probes and/or anticancer drugs. Pharmacokinetic and biodistribution studies confirmed long circulation times (t(1/2) = 21 hours) and efficient accumulation in tumors (up to 15% ID/g) irrespective of the presence of the targeting ligand. Although total accumulations of anti-EGFR immunoliposomes and nontargeted liposomes in EGFR-overexpressing tumors were comparable, only immunoliposomes internalized extensively within tumor cells (92% of analyzed cells versus < 5% for nontargeted liposomes), indicating different mechanisms of delivery at the cellular level. In vivo therapy studies in a series of xenograft models featuring overexpression of EGFR and/or EGFRvIII showed the superiority of immunoliposomal delivery of encapsulated drugs, which included doxorubicin, epirubicin, and vinorelbine. For each of these drugs, anti-EGFR immunoliposome delivery showed significant antitumor effects and was significantly superior to all other treatments, including the corresponding free or liposomal drug (P < 0.001-0.003). We conclude that anti-EGFR immunoliposomes provide efficient and targeted drug delivery of anticancer compounds and may represent a useful new treatment approach for tumors that overexpress the EGFR.