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Nanoalbumin–prodrug conjugates prepared via a thiolation-and-conjugation method improve cancer chemotherapy and immune checkpoint blockade therapy by promoting CD8+ T-cell infiltration
Bioengineering & Translational Medicine ( IF 6.1 ) Pub Date : 2022-07-26 , DOI: 10.1002/btm2.10377
Long Chen 1 , Nuo Xu 1 , Pan Wang 2 , Haichuan Zhu 3 , Zijian Zhang 3 , Zhanqun Yang 1 , Wenyuan Zhang 1 , Hongyan Guo 2 , Jian Lin 1
Affiliation  

Protein–drug conjugates are emerging tools to combat cancers. Here, we adopted an indirect thiolation-and-conjugation method as a general strategy to prepare protein–drug conjugates. We found for the first time that this method led to the formation of nanometric conjugates, probably due to the formation of intermolecular disulfide bonds, which facilitated enhanced uptake by cancer cells. As a proof-of-concept application in cancer therapy, a nanometric albumin–doxorubicin prodrug conjugate (NanoAlb-proDOX) was prepared. The nanometric size promoted its uptake by cancer cells, and the prodrug characteristic defined its selective cytotoxicity toward cancer cells in vitro and reduced side effects in vivo. In multiple tumor xenograft models, nanometric NanoAlb-proDOX showed superior antitumor activity and synergy with immune checkpoint blockade, probably due to the synergistically enhanced tumor CD8+ T-cell infiltration and activation. Hence, the thiolation-and-conjugation strategy may serve as a generally applicable method for preparing drug conjugates, and the proof-of-concept nanometric albumin–doxorubicin conjugate may be a good choice for antitumor therapy with the ability to co-stimulate the efficacy of immune checkpoint blockade.

中文翻译:


通过硫醇化和缀合方法制备的纳米白蛋白-前药缀合物通过促进 CD8+ T 细胞浸润来改善癌症化疗和免疫检查点阻断疗法



蛋白质-药物结合物是对抗癌症的新兴工具。在这里,我们采用间接硫醇化和缀合方法作为制备蛋白质-药物缀合物的一般策略。我们首次发现这种方法导致了纳米缀合物的形成,这可能是由于分子间二硫键的形成,从而促进了癌细胞的增强摄取。作为癌症治疗中的概念验证应用,制备了纳米白蛋白-阿霉素前药缀合物(NanoAlb-proDOX)。纳米尺寸促进了癌细胞对其的摄取,前药特性决定了其在体外对癌细胞的选择性细胞毒性,并减少了体内的副作用。在多个肿瘤异种移植模型中,纳米 NanoAlb-proDOX 显示出优异的抗肿瘤活性以及与免疫检查点阻断的协同作用,这可能是由于协同增强了肿瘤 CD8 + T 细胞浸润和激活。因此,硫醇化和缀合策略可能作为制备药物缀合物的普遍适用的方法,而概念验证的纳米白蛋白-阿霉素缀合物可能是抗肿瘤治疗的一个不错的选择,具有共同刺激疗效的能力免疫检查点封锁。
更新日期:2022-07-26
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