A minimalist multifunctional nano-prodrug for drug resistance reverse and integration with PD-L1 mAb for enhanced immunotherapy of hepatocellular carcinoma
Abstract Clinical treatment of hepatocellular carcinoma (HCC) with 5-fluorouracil (5-FU), the primary anticancer agent, remains unsatisfactory due to the glutathione (GSH)-associated drug resistance and immunosuppressive microenvironment of HCC. To develop a facile yet robust strategy to overcome 5-...
Saved in:
| Main Authors: | , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2024-12-01
|
| Series: | Journal of Nanobiotechnology |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12951-024-03027-w |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850169220886691840 |
|---|---|
| author | Ting Zou Yun Huang Zongtao Zhou Shuangyan He Jia Liu Yalan Chen Hongdu Liu Zhonghui Luo Miaoxin Liu Hua Wei CuiYun Yu |
| author_facet | Ting Zou Yun Huang Zongtao Zhou Shuangyan He Jia Liu Yalan Chen Hongdu Liu Zhonghui Luo Miaoxin Liu Hua Wei CuiYun Yu |
| author_sort | Ting Zou |
| collection | DOAJ |
| description | Abstract Clinical treatment of hepatocellular carcinoma (HCC) with 5-fluorouracil (5-FU), the primary anticancer agent, remains unsatisfactory due to the glutathione (GSH)-associated drug resistance and immunosuppressive microenvironment of HCC. To develop a facile yet robust strategy to overcome 5-FU resistance for enhanced immunotherapy treatment of HCC via all dimensional GSH exhaustion, we report in this study construction of a minimalist prodrug consisting of 5-FU linked to an indoleamine-(2,3)-dioxygenase (IDO) inhibitor (IND) via a disulfide bridge, FU-SS-IND that can further self-assemble into stabilized nanoparticles, FU-SS-IND NPs. Specifically, besides the disulfide linker-induced GSH exhaustion, IND inhibits GSH biosynthesis and enhances the effector function of T cells for turning a “cold” tumor to a “hot” one, which synergistically achieving a tumor inhibition rate (TIR) of 92.5% in a 5-FU resistant mice model. Most importantly, FU-SS-IND NPs could upregulate programmed death ligand 1 (PD-L1) expression on the surface of tumor cells, which enables facile combination with immune checkpoint blockade (ICB) for a ultimate prolonged survival lifetime of 5-FU-resistant tumors-bearing mice. Overall, the minimalist bioreducible nano-prodrug developed herein demonstrates great translatable potential for efficiently reversing drug resistance and enhancing immunotherapy of HCC. |
| format | Article |
| id | doaj-art-add4d632670f43dc85ef0d3b295690a6 |
| institution | OA Journals |
| issn | 1477-3155 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Nanobiotechnology |
| spelling | doaj-art-add4d632670f43dc85ef0d3b295690a62025-08-20T02:20:47ZengBMCJournal of Nanobiotechnology1477-31552024-12-0122111810.1186/s12951-024-03027-wA minimalist multifunctional nano-prodrug for drug resistance reverse and integration with PD-L1 mAb for enhanced immunotherapy of hepatocellular carcinomaTing Zou0Yun Huang1Zongtao Zhou2Shuangyan He3Jia Liu4Yalan Chen5Hongdu Liu6Zhonghui Luo7Miaoxin Liu8Hua Wei9CuiYun Yu10Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, School of Pharmaceutical Science & MOE Key Lab of Rare Pediatric Disease, Hengyang Medical School, University of South ChinaHunan Province Cooperative Innovation Center for Molecular Target New Drug Study, School of Pharmaceutical Science & MOE Key Lab of Rare Pediatric Disease, Hengyang Medical School, University of South ChinaHunan Province Cooperative Innovation Center for Molecular Target New Drug Study, School of Pharmaceutical Science & MOE Key Lab of Rare Pediatric Disease, Hengyang Medical School, University of South ChinaHunan Province Cooperative Innovation Center for Molecular Target New Drug Study, School of Pharmaceutical Science & MOE Key Lab of Rare Pediatric Disease, Hengyang Medical School, University of South ChinaHunan Province Cooperative Innovation Center for Molecular Target New Drug Study, School of Pharmaceutical Science & MOE Key Lab of Rare Pediatric Disease, Hengyang Medical School, University of South ChinaHunan Province Cooperative Innovation Center for Molecular Target New Drug Study, School of Pharmaceutical Science & MOE Key Lab of Rare Pediatric Disease, Hengyang Medical School, University of South ChinaHunan Province Cooperative Innovation Center for Molecular Target New Drug Study, School of Pharmaceutical Science & MOE Key Lab of Rare Pediatric Disease, Hengyang Medical School, University of South ChinaHunan Province Cooperative Innovation Center for Molecular Target New Drug Study, School of Pharmaceutical Science & MOE Key Lab of Rare Pediatric Disease, Hengyang Medical School, University of South ChinaHunan Province Cooperative Innovation Center for Molecular Target New Drug Study, School of Pharmaceutical Science & MOE Key Lab of Rare Pediatric Disease, Hengyang Medical School, University of South ChinaHunan Province Cooperative Innovation Center for Molecular Target New Drug Study, School of Pharmaceutical Science & MOE Key Lab of Rare Pediatric Disease, Hengyang Medical School, University of South ChinaAffiliated Hospital of Hunan Academy of Chinese Medicine, Hunan Academy of Chinese MedicineAbstract Clinical treatment of hepatocellular carcinoma (HCC) with 5-fluorouracil (5-FU), the primary anticancer agent, remains unsatisfactory due to the glutathione (GSH)-associated drug resistance and immunosuppressive microenvironment of HCC. To develop a facile yet robust strategy to overcome 5-FU resistance for enhanced immunotherapy treatment of HCC via all dimensional GSH exhaustion, we report in this study construction of a minimalist prodrug consisting of 5-FU linked to an indoleamine-(2,3)-dioxygenase (IDO) inhibitor (IND) via a disulfide bridge, FU-SS-IND that can further self-assemble into stabilized nanoparticles, FU-SS-IND NPs. Specifically, besides the disulfide linker-induced GSH exhaustion, IND inhibits GSH biosynthesis and enhances the effector function of T cells for turning a “cold” tumor to a “hot” one, which synergistically achieving a tumor inhibition rate (TIR) of 92.5% in a 5-FU resistant mice model. Most importantly, FU-SS-IND NPs could upregulate programmed death ligand 1 (PD-L1) expression on the surface of tumor cells, which enables facile combination with immune checkpoint blockade (ICB) for a ultimate prolonged survival lifetime of 5-FU-resistant tumors-bearing mice. Overall, the minimalist bioreducible nano-prodrug developed herein demonstrates great translatable potential for efficiently reversing drug resistance and enhancing immunotherapy of HCC.https://doi.org/10.1186/s12951-024-03027-w5-FUINDNano-prodrugDrug resistanceGSH exhaustionPD-L1 |
| spellingShingle | Ting Zou Yun Huang Zongtao Zhou Shuangyan He Jia Liu Yalan Chen Hongdu Liu Zhonghui Luo Miaoxin Liu Hua Wei CuiYun Yu A minimalist multifunctional nano-prodrug for drug resistance reverse and integration with PD-L1 mAb for enhanced immunotherapy of hepatocellular carcinoma Journal of Nanobiotechnology 5-FU IND Nano-prodrug Drug resistance GSH exhaustion PD-L1 |
| title | A minimalist multifunctional nano-prodrug for drug resistance reverse and integration with PD-L1 mAb for enhanced immunotherapy of hepatocellular carcinoma |
| title_full | A minimalist multifunctional nano-prodrug for drug resistance reverse and integration with PD-L1 mAb for enhanced immunotherapy of hepatocellular carcinoma |
| title_fullStr | A minimalist multifunctional nano-prodrug for drug resistance reverse and integration with PD-L1 mAb for enhanced immunotherapy of hepatocellular carcinoma |
| title_full_unstemmed | A minimalist multifunctional nano-prodrug for drug resistance reverse and integration with PD-L1 mAb for enhanced immunotherapy of hepatocellular carcinoma |
| title_short | A minimalist multifunctional nano-prodrug for drug resistance reverse and integration with PD-L1 mAb for enhanced immunotherapy of hepatocellular carcinoma |
| title_sort | minimalist multifunctional nano prodrug for drug resistance reverse and integration with pd l1 mab for enhanced immunotherapy of hepatocellular carcinoma |
| topic | 5-FU IND Nano-prodrug Drug resistance GSH exhaustion PD-L1 |
| url | https://doi.org/10.1186/s12951-024-03027-w |
| work_keys_str_mv | AT tingzou aminimalistmultifunctionalnanoprodrugfordrugresistancereverseandintegrationwithpdl1mabforenhancedimmunotherapyofhepatocellularcarcinoma AT yunhuang aminimalistmultifunctionalnanoprodrugfordrugresistancereverseandintegrationwithpdl1mabforenhancedimmunotherapyofhepatocellularcarcinoma AT zongtaozhou aminimalistmultifunctionalnanoprodrugfordrugresistancereverseandintegrationwithpdl1mabforenhancedimmunotherapyofhepatocellularcarcinoma AT shuangyanhe aminimalistmultifunctionalnanoprodrugfordrugresistancereverseandintegrationwithpdl1mabforenhancedimmunotherapyofhepatocellularcarcinoma AT jialiu aminimalistmultifunctionalnanoprodrugfordrugresistancereverseandintegrationwithpdl1mabforenhancedimmunotherapyofhepatocellularcarcinoma AT yalanchen aminimalistmultifunctionalnanoprodrugfordrugresistancereverseandintegrationwithpdl1mabforenhancedimmunotherapyofhepatocellularcarcinoma AT hongduliu aminimalistmultifunctionalnanoprodrugfordrugresistancereverseandintegrationwithpdl1mabforenhancedimmunotherapyofhepatocellularcarcinoma AT zhonghuiluo aminimalistmultifunctionalnanoprodrugfordrugresistancereverseandintegrationwithpdl1mabforenhancedimmunotherapyofhepatocellularcarcinoma AT miaoxinliu aminimalistmultifunctionalnanoprodrugfordrugresistancereverseandintegrationwithpdl1mabforenhancedimmunotherapyofhepatocellularcarcinoma AT huawei aminimalistmultifunctionalnanoprodrugfordrugresistancereverseandintegrationwithpdl1mabforenhancedimmunotherapyofhepatocellularcarcinoma AT cuiyunyu aminimalistmultifunctionalnanoprodrugfordrugresistancereverseandintegrationwithpdl1mabforenhancedimmunotherapyofhepatocellularcarcinoma AT tingzou minimalistmultifunctionalnanoprodrugfordrugresistancereverseandintegrationwithpdl1mabforenhancedimmunotherapyofhepatocellularcarcinoma AT yunhuang minimalistmultifunctionalnanoprodrugfordrugresistancereverseandintegrationwithpdl1mabforenhancedimmunotherapyofhepatocellularcarcinoma AT zongtaozhou minimalistmultifunctionalnanoprodrugfordrugresistancereverseandintegrationwithpdl1mabforenhancedimmunotherapyofhepatocellularcarcinoma AT shuangyanhe minimalistmultifunctionalnanoprodrugfordrugresistancereverseandintegrationwithpdl1mabforenhancedimmunotherapyofhepatocellularcarcinoma AT jialiu minimalistmultifunctionalnanoprodrugfordrugresistancereverseandintegrationwithpdl1mabforenhancedimmunotherapyofhepatocellularcarcinoma AT yalanchen minimalistmultifunctionalnanoprodrugfordrugresistancereverseandintegrationwithpdl1mabforenhancedimmunotherapyofhepatocellularcarcinoma AT hongduliu minimalistmultifunctionalnanoprodrugfordrugresistancereverseandintegrationwithpdl1mabforenhancedimmunotherapyofhepatocellularcarcinoma AT zhonghuiluo minimalistmultifunctionalnanoprodrugfordrugresistancereverseandintegrationwithpdl1mabforenhancedimmunotherapyofhepatocellularcarcinoma AT miaoxinliu minimalistmultifunctionalnanoprodrugfordrugresistancereverseandintegrationwithpdl1mabforenhancedimmunotherapyofhepatocellularcarcinoma AT huawei minimalistmultifunctionalnanoprodrugfordrugresistancereverseandintegrationwithpdl1mabforenhancedimmunotherapyofhepatocellularcarcinoma AT cuiyunyu minimalistmultifunctionalnanoprodrugfordrugresistancereverseandintegrationwithpdl1mabforenhancedimmunotherapyofhepatocellularcarcinoma |