埃坡霉素 B (Epo B) 是一种很有前途的抗肿瘤化合物，在体外可有效对抗各种类型的癌细胞。然而，其对肿瘤细胞的选择性差和治疗窗不足严重限制了其潜在的临床应用。 Affibody 是一类非免疫球蛋白亲和蛋白，具有精确靶向癌细胞上过度表达的分子受体的能力，由于其卓越的亲和特性而受到深入研究。在这项研究中，我们提出了一种靶向纳米剂，它是由亲和体前体通过含有对活性氧 (ROS) 敏感的硫缩酮 (tk) 基团的连接体与 Epo B 缀合而成的。 ZHER2:342-Epo B 亲和体药物缀合物纳米剂 (Z-E ADCN) 的核壳结构，将细胞毒素 Epo B 封装在 ZHER2:342 亲和体冠内，可显着减少对正常器官的副作用。此外，表面丰富的ZHER2:342有效增强了药物的靶向能力和肿瘤蓄积。 Z-E ADCN 可通过 HER2 受体介导的内吞作用被癌细胞内化，随后响应高水平 ROS 释放 Epo B，从而在 HER2 阳性肿瘤模型中产生出色的抗癌功效。© 2024。作者。

Epothilone B (Epo B), a promising antitumor compound effective against various types of cancer cells in vitro. However, its poor selectivity for tumor cells and inadequate therapeutic windows significantly limit its potential clinical application. Affibody is a class of non-immunoglobulin affinity proteins with precise targeting capability to overexpressed molecular receptors on cancer cells, has been intensively investigated due to its exceptional affinity properties. In this study, we present a targeted nanoagent self-assembled from the precursor of an affibody conjugated with Epo B via a linker containing the thioketal (tk) group that is sensitive to reactive oxygen species (ROS). The core-shell structure of the ZHER2:342-Epo B Affibody-Drug Conjugate Nanoagent (Z-E ADCN), with the cytotoxin Epo B encapsulated within the ZHER2:342 affibody corona, leads to significantly reduced side effects on normal organs. Moreover, the abundant presence of ZHER2:342 on the surface effectively enhances the targeting capacity and tumor accumulation of the drug. Z-E ADCN can be internalized by cancer cells via HER2 receptor-mediated endocytosis followed by Epo B release in response to high levels of ROS, resulting in excellent anticancer efficacy in HER2-positive tumor models.© 2024. The Author(s).