Wang Maolin, Shu Xing-Sheng, Li Meiqi, Zhang Yilin, Yao Youli, Huang Xiaoyan, Li Jianna, Wei Pengfei, He Zhendan, Lu Jun, Ying Ying
Department of Physiology, School of Basic Medical Sciences, Shenzhen University Health Science Center, Shenzhen, China.
College of Pharmacy, Shenzhen Technology University, Shenzhen, China.
Front Oncol. 2021 Nov 10;11:737323. doi: 10.3389/fonc.2021.737323. eCollection 2021.
Modifying the structure of anti-tumor chemotherapy drug is of significance to enhance the specificity and efficacy of drug-delivery. A novel proteolysis resistant PD-L1-targeted peptide (PPA1) has been reported to bind to PD-L1 and disrupt the PD-1/PD-L1 interaction, thus appearing as an outstanding tumor-targeting modification of synergistic drug conjugate for effective anti-tumor treatment. However, the combination regimen of coupling PD-L1 polypeptide with chemotherapeutic drug in tumoricidal treatment has not been reported thus far.
We developed a novel synergistic strategy by conjugating PPA1 to doxorubicin (DOX) with a pH sensitive linker that can trigger the release of DOX near acidic tumor tissues. The binding affinity of PPA1-DOX with PD-L1 and the acid-sensitive cleavage of PPA1-DOX were investigated. A mouse xenograft model of colon cancer was used to evaluate the biodistribution, cytotoxicity and anti-tumor activity of PPA1-DOX.
PPA1-DOX construct showed high binding affinity with PD-L1 and specifically enriched within tumor when administered . PPA1-DOX exhibited a significantly lower toxicity and a remarkably higher antitumor activity , as compared with free PPA1, random polypeptide-DOX conjugate, DOX, or 5-FU, respectively. Moreover, increased infiltration of both CD4 and CD8 T cells was found in tumors from PPA1-DOX treated mice.
We describe here for the first time that the dual-functional conjugate PPA1-DOX, which consist of the PD-L1-targeted polypeptide that renders both the tumor-specific drug delivery and inhibitory PD-1/PD-L1 immune checkpoint inhibition, and a cytotoxic agent that is released and kills tumor cells once reaching tumor tissues, thus representing a promising therapeutic option for colon cancer with improved efficacy and reduced toxicity.
修饰抗肿瘤化疗药物的结构对于提高药物递送的特异性和疗效具有重要意义。据报道，一种新型的抗蛋白酶解的程序性死亡配体1（PD-L1）靶向肽（PPA1）可与PD-L1结合并破坏PD-1/PD-L1相互作用，因此作为协同药物偶联物的出色肿瘤靶向修饰用于有效的抗肿瘤治疗。然而，迄今为止，在肿瘤杀伤治疗中偶联PD-L1多肽与化疗药物的联合方案尚未见报道。
我们开发了一种新型的协同策略，即将PPA1与阿霉素（DOX）通过一种pH敏感的连接子进行偶联，该连接子可在酸性肿瘤组织附近触发DOX的释放。研究了PPA1-DOX与PD-L1的结合亲和力以及PPA1-DOX的酸敏裂解情况。使用结肠癌小鼠异种移植模型评估PPA1-DOX的生物分布、细胞毒性和抗肿瘤活性。
PPA1-DOX构建体与PD-L1显示出高结合亲和力，给药后在肿瘤内特异性富集。与游离PPA1、随机多肽-DOX偶联物、DOX或5-氟尿嘧啶相比，PPA1-DOX分别表现出显著更低的毒性和更高的抗肿瘤活性。此外，在接受PPA1-DOX治疗的小鼠的肿瘤中发现CD4和CD8 T细胞的浸润增加。
我们首次在此描述了双功能偶联物PPA1-DOX，它由具有肿瘤特异性药物递送和抑制PD-1/PD-L1免疫检查点抑制作用的PD-L1靶向多肽以及一旦到达肿瘤组织就释放并杀死肿瘤细胞的细胞毒性剂组成，因此代表了一种有前景的治疗结肠癌的选择，具有更高的疗效和更低的毒性。
