在靶向癌症治疗中，使用基于 Mertansine (DM1) 的细胞毒性化合物的抗体药物偶联物依赖于共价键进行药物偶联。因此，蛋白水解消化后释放的细胞毒性 DM1 衍生物的效力比 DM1 低 1000 倍，并且缺乏旁观者效应。为了克服这些限制，我们开发了一种适合通过酸可逆腙键进行生物共轭的 DM1 衍生物（酮-DM1）。使用西妥昔单抗靶向亲和素-核酸-纳米组装体 (ANANAS) 纳米颗粒 (NP) 平台生成其酸可逆腙与生物素 (B-Hz-DM1) 缀合物并测试其功效。 NP 束缚的 B-Hz-DM1 在中性 pH 下稳定，仅在模拟酸性 pH 的内体/溶酶体中释放其活性部分。在体外，NP/Cetux/B-Hz-DM1 组装体对 MDA-MB231 乳腺癌细胞显示出高效能。在体内，B-Hz-DM1 和 NP/Cetux/B-Hz-DM1 均减少肿瘤生长。纳米制剂发挥了显着的主要作用，与原位肿瘤细胞死亡增加相关。 Keto-DM1 是一种很有前途的酸可逆 Mertansine 衍生物，用于癌症治疗中的靶向递送。版权所有 © 2024 Elsevier Inc. 保留所有权利。

In targeted cancer therapy, antibody-drug-conjugates using mertansine (DM1)-based cytotoxic compounds rely on covalent bonds for drug conjugation. Consequently, the cytotoxic DM1 derivative released upon their proteolytic digestion is up to 1000-fold less potent than DM1 and lacks a bystander effect. To overcome these limitations, we developed a DM1 derivative (keto-DM1) suitable for bioconjugation through an acid-reversible hydrazone bond. Its acid-reversible hydrazone conjugate with biotin (B-Hz-DM1) was generated and tested for efficacy using the cetuximab-targeted Avidin-Nucleic-Acid-NanoASsembly (ANANAS) nanoparticle (NP) platform. NP-tethered B-Hz-DM1 is stable at neutral pH and releases its active moiety only in endosome/lysosome mimicking acidic pH. In vitro, the NP/Cetux/B-Hz-DM1 assembly showed high potency on MDA-MB231 breast cancer cells. In vivo both B-Hz-DM1 and NP/Cetux/B-Hz-DM1 reduced tumor growth. A significantly major effect was exerted by the nanoformulation, associated with an increased in situ tumor cell death. Keto-DM1 is a promising acid-reversible mertansine derivative for targeted delivery in cancer therapy.Copyright © 2024 Elsevier Inc. All rights reserved.