Enhanced In Vivo Tumor Detection by Active Tumor Cell Targeting Using Multiple Tumor Receptor-Binding Peptides Presented on Genetically Engineered Human Ferritin Nanoparticles
Enhanced In Vivo Tumor Detection by Active Tumor Cell Targeting Using Multiple Tumor Receptor-Binding Peptides Presented on Genetically Engineered Human Ferritin Nanoparticles
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DOI：
10.1002/smll.201600917
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发表时间：
2016-08-17
期刊：
影响因子：
13.3
通讯作者：
Lee, Jeewon
中科院分区：
文献类型：
--
作者：
Kwon, Koo Chul;Ko, Ho Kyung;Lee, Jeewon
人铁蛋白重链纳米粒子(HFTH)是通过基因工程的方式在其表面呈现肿瘤受体结合肽(亲和体和/或RGD衍生的环肽，这里称为4CRGD)。亲和体和4CRGD分别与人表皮生长因子受体I(EGFR)和人整合素αvβ3特异性和强结合，这两种受体在多种肿瘤细胞上过表达。通过对EGFR高表达的腺癌(MDA-MB-468)和高表达整合素的胶质母细胞瘤细胞(U87 MG)的体外培养，阐明了肿瘤细胞表面受体与工程hFTH上的受体结合肽之间的特异性相互作用是肿瘤细胞靶向的关键。经近红外荧光染料(Cy5.5)标记后，经静脉注射入MDAMB-468或U87 MG荷瘤小鼠体内，可成功地将多肽或同时具有亲和肽和4CRGD的重组hFTH传递到肿瘤中并在肿瘤内保留较长时间。特别是，与仅提供亲和或4CRGD的重组hFTH相比，同时提供亲和和4CRGD的重组hFTH显著提高了对表达异质受体、整合素和EGFR的U87 MG肿瘤的体内检测。与本研究中使用的亲和体和4CRGD一样，还可以将其他多个肿瘤受体结合肽基因导入hFTH表面，以主动靶向具有异源受体的体内肿瘤。
Human ferritin heavy-chain nanoparticle (hFTH) is genetically engineered to present tumor receptor-binding peptides (affibody and/or RGD-derived cyclic peptides, named 4CRGD here) on its surface. The affibody and 4CRGD specifically and strongly binds to human epidermal growth factor receptor I (EGFR) and human integrin alpha v beta 3, respectively, which are overexpressed on various tumor cells. Through in vitro culture of EGFR-overexpressing adenocarcinoma (MDA-MB-468) and integrin-overexpressing glioblastoma cells (U87MG), it is clarified that specific interactions between receptors on tumor cells and receptor-binding peptides on engineered hFTH is critical in active tumor cell targeting. After labeling with the near-infrared fluorescence dye (Cy5.5) and intravenouse injection into MDA-MB-468 or U87MG tumor-bearing mice, the recombinant hFTHs presenting either peptide or both of affibody and 4CRGD are successfully delivered to and retained in the tumor for a prolonged period of time. In particular, the recombinant hFTH presenting both affibody and 4CRGD notably enhances in vivo detection of U87MG tumors that express heterogeneous receptors, integrin and EGFR, compared to the other recombinant hFTHs presenting either affibody or 4CRGD only. Like affibody and 4CRGD used in this study, other multiple tumor receptor-binding peptides can be also genetically introduced to the hFTH surface for actively targeting of in vivo tumors with heterogenous receptors.