An antibody?supermolecule conjugate for tumor-specific targeting of tumoricidal methylated β-cyclodextrin-threaded polyrotaxanes
An antibody?supermolecule conjugate for tumor-specific targeting of tumoricidal methylated β-cyclodextrin-threaded polyrotaxanes
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一种抗体超分子缀合物，用于杀肿瘤甲基化β-环糊精螺纹聚轮烷的肿瘤特异性靶向
DOI：
10.1039/d0tb00575d
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发表时间：
2020
影响因子：
7
通讯作者：
Yui Nobuhiko
中科院分区：
文献类型：
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作者：
Nishida Kei;Tamura Astushi;Kang Tae Woong;Masuda Hiroki;Yui Nobuhiko
我们之前发现，含有甲基化β-环糊精（Me-PRX）的酸不稳定聚轮烷可诱导内质网（ER）应激相关的自噬和自噬细胞死亡。 Me-PRX 诱导的自噬性细胞死亡甚至发生在抗凋亡细胞中；因此，肿瘤靶向 Me-PRX 递送可能是一种有效的癌症治疗方法。在这项研究中，抗体-超分子缀合物由肿瘤特异性抗体和 Me-PRX 组成，旨在实现 Me-PRX 的肿瘤特异性递送。选择曲妥珠单抗（一种针对多种恶性肿瘤中表达的HER2的单克隆抗体）作为肿瘤靶向抗体，将苯基马来酰亚胺基团修饰的Me-PRX（Mal-Me-PRX）与还原的曲妥珠单抗的半胱氨酸残基缀合，获得曲妥珠单抗-Me-PRX缀合物（Tras-Me-PRX）。 Tras-Me-PRX 与表达 HER2 的肿瘤细胞的细胞关联显着大于未修饰的 Me-PRX。此外，与未修饰的 Me-PRX 相比，Tras-Me-PRX 在较低浓度下有效降低了表达 HER2 的肿瘤细胞的活力。总之，抗体-Me-PRX缀合物被认为是一类新型抗体-药物缀合物，有助于癌症的化疗。
We previously found that acid-labile polyrotaxane containing methylated β-cyclodextrin (Me-PRX) induces endoplasmic reticulum (ER) stress-related autophagy and autophagic cell death. Me-PRX-induced autophagic cell death occurs even in apoptosis-resistant cells; tumor-targeted Me-PRX delivery could thus be an effective cancer treatment approach. In this study, antibody–supermolecule conjugates, consisting of a tumor-specific antibody and Me-PRX, were designed to achieve a tumor-specific delivery of Me-PRX. Trastuzumab, a monoclonal antibody against HER2 expressed in various malignant tumors, was selected as a tumor-targeting antibody, and phenyl maleimide group-modified Me-PRX (Mal-Me-PRX) was conjugated to the cysteine residue of the reduced Trastuzumab to obtain a Trastuzumab–Me-PRX conjugate (Tras-Me-PRX). The cellular association of Tras-Me-PRX to HER2-expressing tumor cells was remarkably greater than that of unmodified Me-PRX. Moreover, Tras-Me-PRX effectively reduced the viability of HER2-expressing tumor cells at a lower concentration compared to the unmodified Me-PRX. In conclusion, antibody–Me-PRX conjugates are regarded as a new class of antibody–drug conjugates that would contribute to the chemotherapy of cancers.