Institute of Molecular Medicine, College of Life and Health Sciences, Northeastern University, Shenyang110167, China.
State Key Laboratory of Drug Research, Molecular Imaging Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai201203, China.
Mol Pharm. 2023 Feb 6;20(2):1394-1403. doi: 10.1021/acs.molpharmaceut.2c00964. Epub 2023 Jan 20.
Molecular targets serve a crucial role in drug development. Herein, we discovered a novel peptide that can specifically target the human epidermal growth factor receptor 2 (HER2) and thus named it Herceptide. In our study, Herceptide was conjugated to the near-infrared fluorescent dye indocyanine green (ICG) to obtain a probe, ICG-Herceptide. Importantly, specific binding to HER2 was revealed by molecular docking, surface plasmon resonance analysis, and competition assays. The probe showed high binding affinity ( = 1.03 nM) and fast binding property ( = 0.44 min). In vivo near-infrared window two (NIR-II, 1000-1700 nm) imaging in HER2-overexpressed SKOV3 tumor-bearing mice demonstrated a high tumor-to-normal tissue signal ratio (T/N = 7.3) at 8 h postinjection. In the blocking study, ICG-Herceptide coinjected with Herceptide only showed a weak tumor signal. In other HER2 high-expression tumors, such as non-small-cell lung cancer A549 and gastric cancer MKN45, the tumor-to-normal tissue signal ratios (T/N) were 4.1 and 4.7, respectively. In contrast, HER2 low-expression tumor MDAMB231 shows no imaging contrast between the tumor and normal tissues. Furthermore, tumor resection was successfully performed under the guidance of the ICG-Herceptide-based NIR-II imaging in subcutaneous SKOV3 mice models. The biocompatibility study indicated that the probe had no observable toxicity to cells and tissues. Overall, these results demonstrate that ICG-Herceptide is a promising optical probe for the diagnosis and localization of HER2-overexpressing tumors. Moreover, Herceptide is a novel HER2-targeting peptide and can be further used for developing theranostic agents.
分子靶标在药物开发中起着至关重要的作用。在此，我们发现了一种新型肽，它可以特异性靶向人表皮生长因子受体 2（HER2），因此将其命名为 Herceptide。在我们的研究中，将 Herceptide 与近红外荧光染料吲哚菁绿（ICG）缀合以获得探针 ICG-Herceptide。重要的是，分子对接、表面等离子体共振分析和竞争实验表明，该探针具有特异性结合 HER2 的能力。该探针具有高结合亲和力（=1.03 nM）和快速结合特性（=0.44 min）。在 HER2 过表达 SKOV3 荷瘤小鼠的体内近红外二区（NIR-II，1000-1700nm）成像中，注射后 8 小时肿瘤与正常组织的信号比（T/N=7.3）较高。在阻断研究中，ICG-Herceptide 与 Herceptide 共注射仅显示出较弱的肿瘤信号。在其他 HER2 高表达肿瘤中，如非小细胞肺癌 A549 和胃癌 MKN45，肿瘤与正常组织的信号比（T/N）分别为 4.1 和 4.7。相比之下，HER2 低表达肿瘤 MDAMB231 肿瘤与正常组织之间没有成像对比。此外，在皮下 SKOV3 小鼠模型中，成功地在 ICG-Herceptide 基 NIR-II 成像引导下进行了肿瘤切除。生物相容性研究表明，该探针对细胞和组织没有观察到毒性。总之，这些结果表明，ICG-Herceptide 是一种很有前途的用于诊断和定位 HER2 过表达肿瘤的光学探针。此外，Herceptide 是一种新型的 HER2 靶向肽，可进一步用于开发治疗诊断一体化药物。
