Nano-Econazole Enhanced PD-L1 Checkpoint Blockade for Synergistic Antitumor Immunotherapy against Pancreatic Ductal Adenocarcinoma

作者全名："Li, Qiong; Qin, Siyuan; Tian, Hailong; Liu, Ruolan; Qiao, Ling; Liu, Shanshan; Li, Bowen; Yang, Mei; Shi, Jiayan; Nice, Edouard C.; Li, Jingquan; Lang, Tingyuan; Huang, Canhua"

作者地址："[Li, Qiong; Qin, Siyuan; Tian, Hailong; Li, Bowen; Yang, Mei; Shi, Jiayan; Huang, Canhua] Sichuan Univ, West China Sch Basic Med Sci & Forens Med, State Key Lab Biotherapy, Chengdu 610041, Peoples R China; [Li, Qiong; Qin, Siyuan; Tian, Hailong; Li, Bowen; Yang, Mei; Shi, Jiayan; Huang, Canhua] Sichuan Univ, Canc Ctr, Chengdu 610041, Peoples R China; [Li, Qiong; Qin, Siyuan; Tian, Hailong; Li, Bowen; Yang, Mei; Shi, Jiayan; Huang, Canhua] Sichuan Univ, West China Hosp, Chengdu 610041, Peoples R China; [Li, Qiong; Qin, Siyuan; Tian, Hailong; Li, Bowen; Yang, Mei; Shi, Jiayan; Huang, Canhua] Collaborat Innovat Ctr Biotherapy, Chengdu 610041, Peoples R China; [Liu, Ruolan; Qiao, Ling; Huang, Canhua] Chengdu Univ Tradit Chinese Med, Sch Basic Med Sci, Chengdu 611137, Peoples R China; [Liu, Shanshan] Zunyi Med Univ, Sch Pharm, Zunyi 563006, Peoples R China; [Nice, Edouard C.] Monash Univ, Dept Biochem & Mol Biol, Clayton, Vic 3800, Australia; [Li, Jingquan] Hainan Med Univ, Dept Gastrointestinal Oncol Surg, Affiliated Hosp 1, Haikou 570216, Hainan, Peoples R China; [Lang, Tingyuan] Chongqing Univ Canc Hosp, Dept Gynecol Oncol, Chongqing 400030, Peoples R China; [Lang, Tingyuan] Chongqing Canc Inst, Chongqing 400030, Peoples R China; [Lang, Tingyuan] Chongqing Canc Hosp, Chongqing 400030, Peoples R China; [Lang, Tingyuan] Chongqing Med Univ, Affiliated Hosp 1, Reprod Med Ctr, Chongqing 400042, Peoples R China"

通信作者："Huang, CH (通讯作者)，Sichuan Univ, West China Sch Basic Med Sci & Forens Med, State Key Lab Biotherapy, Chengdu 610041, Peoples R China.; Huang, CH (通讯作者)，Sichuan Univ, Canc Ctr, Chengdu 610041, Peoples R China.; Huang, CH (通讯作者)，Sichuan Univ, West China Hosp, Chengdu 610041, Peoples R China.; Huang, CH (通讯作者)，Collaborat Innovat Ctr Biotherapy, Chengdu 610041, Peoples R China.; Huang, CH (通讯作者)，Chengdu Univ Tradit Chinese Med, Sch Basic Med Sci, Chengdu 611137, Peoples R China.; Li, JQ (通讯作者)，Hainan Med Univ, Dept Gastrointestinal Oncol Surg, Affiliated Hosp 1, Haikou 570216, Hainan, Peoples R China.; Lang, TY (通讯作者)，Chongqing Univ Canc Hosp, Dept Gynecol Oncol, Chongqing 400030, Peoples R China.; Lang, TY (通讯作者)，Chongqing Canc Inst, Chongqing 400030, Peoples R China.; Lang, TY (通讯作者)，Chongqing Canc Hosp, Chongqing 400030, Peoples R China.; Lang, TY (通讯作者)，Chongqing Med Univ, Affiliated Hosp 1, Reprod Med Ctr, Chongqing 400042, Peoples R China."

来源：SMALL

ESI学科分类：MATERIALS SCIENCE

WOS号：WOS:000946687500001

JCR分区：Q1

影响因子：13

年份：2023

卷号：　

期号：　

开始页：　

结束页：　

文献类型：Article; Early Access

关键词：chemophototherapy; econazole; immunotherapy; pancreatic ductal adenocarcinoma; PD-L1 blockade

摘要："Insufficienct T lymphocyte infiltration and unresponsiveness to immune checkpoint blockade therapy are still major difficulties for the clinical treatment of pancreatic ductal adenocarcinoma (PDAC). Although econazole has shown promise in inhibiting PDAC growth, its poor bioavailability and water solubility limit its potential as a clinical therapy for PDAC. Furthermore, the synergistic role of econazole and biliverdin in immune checkpoint blockade therapy in PDAC remains elusive and challenging. Herein, a chemo-phototherapy nanoplatform is designed by which econazole and biliverdin can be co-assembled (defined as FBE NPs), which significantly improve the poor water solubility of econazole and enhance the efficacy of PD-L1 checkpoint blockade therapy against PDAC. Mechanistically, econazole and biliverdin are directly released into the acidic cancer microenvironment, to activate immunogenic cell death via biliverdin-induced PTT/PDT and boost the immunotherapeutic response of PD-L1 blockade. In addition, econazole simultaneously enhances PD-L1 expression to sensitize anti-PD-L1 therapy, leading to suppression of distant tumors, long-term immune memory effects, improved dendritic cell maturation, and tumor infiltration of CD8(+)T lymphocytes. The combined FBE NPs and alpha-PDL1 show synergistic antitumor efficacy. Collectively, FBE NPs show excellent biosafety and antitumor efficacy by combining chemo-phototherapy with PD-L1 blockade, which has promising potential in a precision medicine approach as a PDAC treatment strategy."

基金机构："National Key Research and Development Project of China [2020YFA0509400]; National Natural Science Foundation of China [81821002, 82130082]; Guangdong Basic and Applied Basic Research Foundation [2019B030302012]; 1.3.5 project for disciplines of excellence [ZYGD22007]; Chongqing Science & Technology Bureau [CSTB2022NSCQ-MSX1413]"

基金资助正文："This work was supported by National Key Research and Development Project of China (2020YFA0509400), National Natural Science Foundation of China (81821002, 82130082), Guangdong Basic and Applied Basic Research Foundation(2019B030302012), 1.3.5 project for disciplines of excellence (ZYGD22007), Chongqing Science & Technology Bureau (CSTB2022NSCQ-MSX1413). Scheme~1 was created with BioRender.com."