Targeted Nanobubbles of PD-L1 mAb Combined with Doxorubicin as a Synergistic Tumor Repressor in Hepatocarcinoma
Yezi Chen,1,2,* Xiaoqin Luo,2,3,* Yun Liu,4 Yunlei Zou,1,2 Shiqi Yang,1,2 Chaoqi Liu,1,2 Yun Zhao1,2 1Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, China Three Gorges University, Yichang, People’s Republic of China; 2Medical College of China Three Gorges Universit...
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| Format: | Article |
| Language: | English |
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Dove Medical Press
2022-09-01
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| Series: | International Journal of Nanomedicine |
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| Online Access: | https://www.dovepress.com/targeted-nanobubbles-of-pd-l1-mab-combined-with-doxorubicin-as-a-syner-peer-reviewed-fulltext-article-IJN |
| _version_ | 1797998072631918592 |
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| author | Chen Y Luo X Liu Y Zou Y Yang S Liu C Zhao Y |
| author_facet | Chen Y Luo X Liu Y Zou Y Yang S Liu C Zhao Y |
| author_sort | Chen Y |
| collection | DOAJ |
| description | Yezi Chen,1,2,* Xiaoqin Luo,2,3,* Yun Liu,4 Yunlei Zou,1,2 Shiqi Yang,1,2 Chaoqi Liu,1,2 Yun Zhao1,2 1Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, China Three Gorges University, Yichang, People’s Republic of China; 2Medical College of China Three Gorges University, Yichang, People’s Republic of China; 3Department of Medical Imaging Center, Renmin Hospital Affiliated to Hubei University of Medicine, Shiyan, People’s Republic of China; 4Department of Ultrasonography, Yichang Central People’s Hospital, Yichang, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yun Zhao; Chaoqi Liu, Medical College of China Three Gorges, University, Yichang, People’s Republic of China, Email zhaoyun@ctgu.edu.cn; ctgulcq@163.comPurpose: Ultrasound nanobubbles (NBs) can kill tumor cells, mediated by their effects of cavitation and acoustic perforation through ultrasound, while as novel drug carriers, biomaterial-modified NBs release drugs at a target region. In this work, the ultrasound NBs bridged by biotin-streptavidin were prepared simultaneously to be loaded with both programmed death ligand 1 monoclonal antibody (PD-L1 mAb) and doxorubicin (DOX), which are immune checkpoint inhibitors (ICIs) and chemotherapeutic agents, to synergize immunotherapy and chemotherapy combined with sonodynamic therapy (SDT).Methods: The PD-L1 mAb/DOX NBs, using bridging affinity biotin (BRAB) technology as a bridge, were prepared by thin-film hydration and mechanical oscillation for the targeted delivery of biotinylated PD-L1 mAb and DOX. Characterization and pharmacokinetic studies of PD-L1 mAb/DOX NBs were performed in vitro and in vivo. The antitumor effect of ultrasound-mediated PD-L1 mAb/DOX-NBs was studied in the subcutaneously transplanted tumor of the H22 hepatoma model, and the mechanism of synergistic tumor repression was investigated.Results: The data of in vitro targeting experiments, contrast-enhanced ultrasound imaging (CEUS), in vivo imaging of the small animals imaging system (IVIS), and frozen sections showed that PD-L1 mAb/DOX-NBs have well-targeted aggregation in the tumor. By observing tumor inhibition rate, tissue cell apoptosis, and apoptosis-related gene and protein expression, the PD-L1 mAb/DOX-NBs group showed the best immunotherapy effects, and its tumor volume and mass inhibition rates were about 69.64% and 75.97%, respectively (P < 0.01). Therefore, blocking the PD-1/PD-L1 pathway could improve immune cells’ tumor-killing ability. Antitumor immune cytokines were further enhanced when combined with DOX-induced tumor cell apoptosis and immunogenic cell death (ICD).Conclusion: In summary, ultrasound-mediated PD-L1 mAb/DOX-NBs showed significant synergistic antitumor effects, providing a potential combined immunotherapy strategy for HCC.Keywords: ultrasound targeted nanobubble destruction, tumor immune therapy, immune checkpoint inhibitors, immunogenic cell death, drug delivery |
| first_indexed | 2024-04-11T10:42:41Z |
| format | Article |
| id | doaj.art-e2842d5e055d49d7bd543bbeb66192a2 |
| institution | Directory Open Access Journal |
| issn | 1178-2013 |
| language | English |
| last_indexed | 2024-04-11T10:42:41Z |
| publishDate | 2022-09-01 |
| publisher | Dove Medical Press |
| record_format | Article |
| series | International Journal of Nanomedicine |
| spelling | doaj.art-e2842d5e055d49d7bd543bbeb66192a22022-12-22T04:29:08ZengDove Medical PressInternational Journal of Nanomedicine1178-20132022-09-01Volume 173989400878016Targeted Nanobubbles of PD-L1 mAb Combined with Doxorubicin as a Synergistic Tumor Repressor in HepatocarcinomaChen YLuo XLiu YZou YYang SLiu CZhao YYezi Chen,1,2,* Xiaoqin Luo,2,3,* Yun Liu,4 Yunlei Zou,1,2 Shiqi Yang,1,2 Chaoqi Liu,1,2 Yun Zhao1,2 1Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, China Three Gorges University, Yichang, People’s Republic of China; 2Medical College of China Three Gorges University, Yichang, People’s Republic of China; 3Department of Medical Imaging Center, Renmin Hospital Affiliated to Hubei University of Medicine, Shiyan, People’s Republic of China; 4Department of Ultrasonography, Yichang Central People’s Hospital, Yichang, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yun Zhao; Chaoqi Liu, Medical College of China Three Gorges, University, Yichang, People’s Republic of China, Email zhaoyun@ctgu.edu.cn; ctgulcq@163.comPurpose: Ultrasound nanobubbles (NBs) can kill tumor cells, mediated by their effects of cavitation and acoustic perforation through ultrasound, while as novel drug carriers, biomaterial-modified NBs release drugs at a target region. In this work, the ultrasound NBs bridged by biotin-streptavidin were prepared simultaneously to be loaded with both programmed death ligand 1 monoclonal antibody (PD-L1 mAb) and doxorubicin (DOX), which are immune checkpoint inhibitors (ICIs) and chemotherapeutic agents, to synergize immunotherapy and chemotherapy combined with sonodynamic therapy (SDT).Methods: The PD-L1 mAb/DOX NBs, using bridging affinity biotin (BRAB) technology as a bridge, were prepared by thin-film hydration and mechanical oscillation for the targeted delivery of biotinylated PD-L1 mAb and DOX. Characterization and pharmacokinetic studies of PD-L1 mAb/DOX NBs were performed in vitro and in vivo. The antitumor effect of ultrasound-mediated PD-L1 mAb/DOX-NBs was studied in the subcutaneously transplanted tumor of the H22 hepatoma model, and the mechanism of synergistic tumor repression was investigated.Results: The data of in vitro targeting experiments, contrast-enhanced ultrasound imaging (CEUS), in vivo imaging of the small animals imaging system (IVIS), and frozen sections showed that PD-L1 mAb/DOX-NBs have well-targeted aggregation in the tumor. By observing tumor inhibition rate, tissue cell apoptosis, and apoptosis-related gene and protein expression, the PD-L1 mAb/DOX-NBs group showed the best immunotherapy effects, and its tumor volume and mass inhibition rates were about 69.64% and 75.97%, respectively (P < 0.01). Therefore, blocking the PD-1/PD-L1 pathway could improve immune cells’ tumor-killing ability. Antitumor immune cytokines were further enhanced when combined with DOX-induced tumor cell apoptosis and immunogenic cell death (ICD).Conclusion: In summary, ultrasound-mediated PD-L1 mAb/DOX-NBs showed significant synergistic antitumor effects, providing a potential combined immunotherapy strategy for HCC.Keywords: ultrasound targeted nanobubble destruction, tumor immune therapy, immune checkpoint inhibitors, immunogenic cell death, drug deliveryhttps://www.dovepress.com/targeted-nanobubbles-of-pd-l1-mab-combined-with-doxorubicin-as-a-syner-peer-reviewed-fulltext-article-IJNultrasound targeted nanobubble destructiontumor immune therapyimmune checkpoint inhibitorsimmunogenic cell deathdrug delivery |
| spellingShingle | Chen Y Luo X Liu Y Zou Y Yang S Liu C Zhao Y Targeted Nanobubbles of PD-L1 mAb Combined with Doxorubicin as a Synergistic Tumor Repressor in Hepatocarcinoma International Journal of Nanomedicine ultrasound targeted nanobubble destruction tumor immune therapy immune checkpoint inhibitors immunogenic cell death drug delivery |
| title | Targeted Nanobubbles of PD-L1 mAb Combined with Doxorubicin as a Synergistic Tumor Repressor in Hepatocarcinoma |
| title_full | Targeted Nanobubbles of PD-L1 mAb Combined with Doxorubicin as a Synergistic Tumor Repressor in Hepatocarcinoma |
| title_fullStr | Targeted Nanobubbles of PD-L1 mAb Combined with Doxorubicin as a Synergistic Tumor Repressor in Hepatocarcinoma |
| title_full_unstemmed | Targeted Nanobubbles of PD-L1 mAb Combined with Doxorubicin as a Synergistic Tumor Repressor in Hepatocarcinoma |
| title_short | Targeted Nanobubbles of PD-L1 mAb Combined with Doxorubicin as a Synergistic Tumor Repressor in Hepatocarcinoma |
| title_sort | targeted nanobubbles of pd l1 mab combined with doxorubicin as a synergistic tumor repressor in hepatocarcinoma |
| topic | ultrasound targeted nanobubble destruction tumor immune therapy immune checkpoint inhibitors immunogenic cell death drug delivery |
| url | https://www.dovepress.com/targeted-nanobubbles-of-pd-l1-mab-combined-with-doxorubicin-as-a-syner-peer-reviewed-fulltext-article-IJN |
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