Pharmaceutical and Pharmacological Sciences Dept (DSF), University of Padova, Via Marzolo, 5. 35131 Padova, Italy.
Molecular and Translational Medicine Dept (DMMT), University of Brescia, v.le Europa 11, 25121 Brescia, Italy.
Nanomedicine. 2024 Nov;62:102784. doi: 10.1016/j.nano.2024.102784. Epub 2024 Sep 3.
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.
在靶向癌症治疗中，使用美登素（DM1）为基础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，它们的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缀合的 DM1 衍生物（酮-DM1）。它的与生物素（B-Hz-DM1）的酸可逆腙缀合物被生成并使用西妥昔单抗靶向的 Avidin-Nucleic-Acid-NanoASsembly（ANANAS）纳米颗粒（NP）平台进行功效测试。在中性 pH 值下，NP 连接的 B-Hz-DM1 稳定，并且仅在模拟内体/溶酶体酸性 pH 值的情况下释放其活性部分。在体外，NP/Cetux/B-Hz-DM1 组装对 MDA-MB231 乳腺癌细胞显示出高效力。在体内，B-Hz-DM1 和 NP/Cetux/B-Hz-DM1 均降低了肿瘤生长。纳米制剂发挥了显著的主要作用，与原位肿瘤细胞死亡的增加相关。酮-DM1 是一种有前途的酸可逆美登素衍生物，可用于癌症治疗中的靶向递送。
