Wang Lei, Zhou Xusha, Zou Weixuan, Wu Yinglin, Zhao Jing, Chen Xiaoqing, Zhou Grace Guoying
School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, 511436, Guangdong, China.
Shenzhen International Institute for Biomedical Research, Longhua District, 1301 Guanguang Rd. 3F Building 1-B, Silver Star Hi-tech Park, Shenzhen, 518116, Guangdong, China.
J Nanobiotechnology. 2020 Oct 27;18(1):153. doi: 10.1186/s12951-020-00711-5.
Exosomes are small, cellular membrane-derived vesicles with a diameter of 50-150 nm. Exosomes are considered ideal drug delivery systems with a wide range of applications in various diseases, including cancer. However, nonspecific delivery of therapeutic agents by exosomes in vivo remains challenging. Human epidermal growth factor receptor 2 (HER2) is an epidermal growth factor receptor tyrosine kinase, and its overexpression is usually associated with cell survival and tumor progression in various cancers. In this study, we aim to develop novel exosomes with dual HER2-targeting ability as a nanoparticle delivery vehicle to enhance antitumor efficacy in vivo.
Here, we report the generation of two kinds of exosomes carrying miRNAs designed to block HER2 synthesis, which consequently showed a distinct anti-tumor effect. The 293-miR-HER2 exosomes package and deliver miRNAs targeting HER2 to recipient cells to block HER2 synthesis. The anti-tumor effect of these exosomes on cancer cells dependent on HER2 for survival but do not affect cells that lack HER2 or that are engineered to express HER2 but are not dependent on it for survival. In contrast, 293-miR-XS-HER2 exosomes carry an additional peptide, which enables them to adhere to HER2 on the surface of cancer cells. Consequently, these exosomes preferentially enter these cells with surface expression of HER2 and further displayed a tumoricidal effect. The 293-miR-XS-HER2 exosomes are significantly more effective than the 293-miR-HER2 exosomes in shrinking HER2-positive tumors implanted in mice.
Collectively, as novel antitumor drug delivery vehicles, HER2 dual-targeting exosomes exhibit increased target-specific delivery efficiency and can be further utilized to develop new nanoparticle-based targeted therapies.
外泌体是直径为50 - 150纳米的源自细胞膜的小囊泡。外泌体被认为是理想的药物递送系统，在包括癌症在内的各种疾病中具有广泛应用。然而，外泌体在体内对治疗剂的非特异性递送仍然具有挑战性。人表皮生长因子受体2（HER2）是一种表皮生长因子受体酪氨酸激酶，其过表达通常与各种癌症中的细胞存活和肿瘤进展相关。在本研究中，我们旨在开发具有双重HER2靶向能力的新型外泌体作为纳米颗粒递送载体，以增强体内抗肿瘤疗效。
在此，我们报告了两种携带旨在阻断HER2合成的miRNA的外泌体的产生，其结果显示出明显的抗肿瘤作用。293-miR-HER2外泌体将靶向HER2的miRNA包装并递送至受体细胞以阻断HER2合成。这些外泌体对依赖HER2存活的癌细胞具有抗肿瘤作用，但不影响缺乏HER2或经工程改造表达HER2但不依赖其存活的细胞。相比之下，293-miR-XS-HER2外泌体携带一种额外的肽，使其能够粘附在癌细胞表面的HER2上。因此，这些外泌体优先进入具有HER2表面表达的这些细胞，并进一步显示出杀肿瘤作用。在缩小植入小鼠体内的HER2阳性肿瘤方面，293-miR-XS-HER2外泌体比293-miR-HER2外泌体显著更有效。
总体而言，作为新型抗肿瘤药物递送载体，HER2双重靶向外泌体表现出提高的靶向特异性递送效率，并可进一步用于开发基于纳米颗粒的新型靶向疗法。
