A Novel Strategy Conjugating PD-L1 Polypeptide With Doxorubicin Alleviates Chemotherapeutic Resistance and Enhances Immune Response in Colon Cancer.
A Novel Strategy Conjugating PD-L1 Polypeptide With Doxorubicin Alleviates Chemotherapeutic Resistance and Enhances Immune Response in Colon Cancer.
复制标题
PD-L1 多肽与阿霉素结合的新策略可减轻结肠癌的化疗耐药性并增强免疫反应
DOI：
10.3389/fonc.2021.737323
复制
发表时间：
2021
影响因子：
4.7
通讯作者：
Ying Y
中科院分区：
文献类型：
--
作者：
Wang M;Shu XS;Li M;Zhang Y;Yao Y;Huang X;Li J;Wei P;He Z;Lu J;Ying Y
修饰抗肿瘤化疗药物的结构对提高药物传递的特异性和有效性具有重要意义。一种新型的抗蛋白水解性PD-L1靶向多肽(PPA1)可以与PD-L1结合并破坏PD-1/PD-L1相互作用，从而成为有效抗肿瘤治疗的协同药物结合物的一种突出的肿瘤靶向修饰。然而，将PD-L1多肽与化疗药物偶联用于杀瘤治疗的联合方案尚未见报道。我们开发了一种新的协同策略，通过将PPA1与阿霉素(DOX)结合在一个pH敏感的连接物上，可以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的酸敏性切割。采用小鼠结肠癌移植瘤模型，评价了PPA1-DOX的生物分布、细胞毒性和抗肿瘤活性。PPA1-DOX在体外与PD-L1有较高的结合亲和力，体内给药后可特异性地在肿瘤内富集。与游离PPA1、随机多肽-DOX结合物、DOX或5-FU相比，PPA1-DOX的毒性显著降低，体内抗肿瘤活性显著增强。此外，在PPA1-DOX治疗的小鼠肿瘤中发现CD4+和CD8+T细胞的渗透增加。我们在这里首次描述了双功能结合物PPA1-DOX，它由PD-L1靶向多肽和细胞毒剂组成，其中PD-L1靶向多肽提供肿瘤特异性药物传递和抑制PD-1/PD-L1免疫检查点抑制，以及一种细胞毒剂，一旦到达肿瘤组织就会释放并杀死肿瘤细胞，因此是一种有希望的结肠癌治疗方案，具有更高的疗效和更低的毒性。
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 in vitro and specifically enriched within tumor when administered in vivo. PPA1-DOX exhibited a significantly lower toxicity and a remarkably higher antitumor activity in vivo, 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.
登录
查看更多内容
克服感染和癌症中的T细胞耗尽。
影响因子：
16.8
作者：
Pauken KE;Wherry EJ
通讯作者：
Wherry EJ
影响因子：
64.8
作者：
Shankaran, V;Ikeda, H;Schreiber, RD
通讯作者：
Schreiber, RD
DOI：
10.1080/14756366.2018.1465417
发表时间：
2018-12
影响因子：
5.6
作者：
Lu J;Wang M;Wang Z;Fu Z;Lu A;Zhang G
通讯作者：
Zhang G
DOI：
10.1073/pnas.0712278105
发表时间：
2008-02-26
影响因子：
11.1
作者：
Lin, David Yin-Wei;Tanaka, Yoshimasa;Garboczi, David N.
通讯作者：
Garboczi, David N.
用于癌症免疫治疗的 D 肽拮抗剂阻断 PD-1/PD-L1 相互作用。
影响因子：
16.6
作者：
Chang, Hao-Nan;Liu, Bei-Yuan;Gao, Yan-Feng
通讯作者：
Gao, Yan-Feng