Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005, China.
J Transl Med. 2012 Jul 20;10:148. doi: 10.1186/1479-5876-10-148.
Aptamer-based tumor targeted drug delivery system is a promising approach that may increase the efficacy of chemotherapy and reduce the related toxicity. HER2 protein is an attractive target for tumor-specific drug delivery because of its overexpression in multiple malignancies, including breast, gastric, ovarian, and lung cancers.
In this paper, we developed a new HER2 aptamer (HB5) by using systematic evolution of ligands by exponential enrichment technology (SELEX) and exploited its role as a targeting ligand for delivering doxorubicin (Dox) to breast cancer cells in vitro.
The selected aptamer was an 86-nucleotide DNA molecule that bound to an epitope peptide of HER2 with a Kd of 18.9 nM. The aptamer also bound to the extracellular domain (ECD) of HER2 protein with a Kdof 316 nM, and had minimal cross reactivity to albumin or trypsin. In addition, the aptamer was found to preferentially bind to HER2-positive but not HER2-negative breast cancer cells. An aptamer-doxorubicin complex (Apt-Dox) was formulated by intercalating Dox into the DNA structure of HB5. The Apt-Dox complex could selectively deliver Dox to HER2-positive breast cancer cells while reducing the drug intake by HER2-negative cells in vitro. Moreover, Apt-Dox retained the cytotoxicity of Dox against HER2-positive breast cancer cells, but reduced the cytotoxicity to HER2-negative cells.
The results suggest that the selected HER2 aptamer may have application potentials in targeted therapy against HER2-positive breast cancer cells.
基于适配体的肿瘤靶向药物传递系统是一种很有前途的方法，它可以提高化疗的疗效，降低相关毒性。HER2 蛋白是肿瘤特异性药物传递的一个有吸引力的靶点，因为它在多种恶性肿瘤中过度表达，包括乳腺癌、胃癌、卵巢癌和肺癌。
在本文中，我们使用指数富集配体系统进化技术（SELEX）开发了一种新的 HER2 适配体（HB5），并利用其作为靶向配体将阿霉素（Dox）递送到体外乳腺癌细胞。
所选的适配体是一个 86 个核苷酸的 DNA 分子，与 HER2 的一个表位肽结合，Kd 为 18.9 nM。该适配体还与 HER2 蛋白的细胞外结构域（ECD）结合，Kd 为 316 nM，与白蛋白或胰蛋白酶的交叉反应性很小。此外，该适配体被发现优先与 HER2 阳性而非 HER2 阴性乳腺癌细胞结合。通过将 Dox 插入 HB5 的 DNA 结构中，制备了适配体-阿霉素复合物（Apt-Dox）。Apt-Dox 复合物可以选择性地将 Dox 递送到 HER2 阳性乳腺癌细胞，同时减少体外 HER2 阴性细胞对药物的摄取。此外，Apt-Dox 保留了 Dox 对 HER2 阳性乳腺癌细胞的细胞毒性，但降低了对 HER2 阴性细胞的细胞毒性。
研究结果表明，所选的 HER2 适配体可能在针对 HER2 阳性乳腺癌细胞的靶向治疗中有应用潜力。
