Amplified antitumor efficacy by a targeted drug retention and chemosensitization strategy-based “combo” nanoagent together with PD-L1 blockade in reversing multidrug resistance
Abstract Background Recent studies have demonstrated that multidrug resistance (MDR) is a critical factor in the low efficacy of cancer chemotherapy. The main mechanism of MDR arises from the overexpression of P-glycoprotein (P-gp), which actively enhances drug efflux and limits the effectiveness of...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2021-07-01
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| Series: | Journal of Nanobiotechnology |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12951-021-00947-9 |
| _version_ | 1798027074469888000 |
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| author | Weixi Jiang Lei Su Meng Ao Xun Guo Chen Cheng Yuanli Luo Zhuoyan Xie Xingyue Wang Junrui Wang Shuling Liu Yang Cao Pan Li Zhigang Wang Haitao Ran Zhiyi Zhou Jianli Ren |
| author_facet | Weixi Jiang Lei Su Meng Ao Xun Guo Chen Cheng Yuanli Luo Zhuoyan Xie Xingyue Wang Junrui Wang Shuling Liu Yang Cao Pan Li Zhigang Wang Haitao Ran Zhiyi Zhou Jianli Ren |
| author_sort | Weixi Jiang |
| collection | DOAJ |
| description | Abstract Background Recent studies have demonstrated that multidrug resistance (MDR) is a critical factor in the low efficacy of cancer chemotherapy. The main mechanism of MDR arises from the overexpression of P-glycoprotein (P-gp), which actively enhances drug efflux and limits the effectiveness of chemotherapeutic agents. Results In this study, we fabricated a “combo” nanoagent equipping with triple synergistic strategies for enhancing antitumor efficacy against MDR cells. Tumor homing-penetrating peptide endows the nanosystem with targeting and penetrating capabilities in the first stage of tumor internalization. The abundant amine groups of polyethylenimine (PEI)-modified nanoparticles then trigger a proton sponge effect to promote endo/lysosomal escape, which enhances the intracellular accumulation and retention of anticancer drugs. Furthermore, copper tetrakis(4-carboxyphenyl)porphyrin (CuTCPP) encapsulated in the nanosystem, effectively scavenges endogenous glutathione (GSH) to reduce the detoxification mediated by GSH and sensitize the cancer cells to drugs, while simultaneously serving as a photoacoustic imaging (PAI) contrast agent for image visualization. Moreover, we also verify that these versatile nanoparticles in combination with PD-1/PD-L1 blockade therapy can not only activate immunological responses but also inhibit P-gp expression to obliterate primary and metastatic tumors. Conclusion This work shows a significant enhancement in therapeutic efficacy against MDR cells and syngeneic tumors by using multiple MDR reversing strategies compared to an equivalent dose of free paclitaxel. Graphic Abstract |
| first_indexed | 2024-04-11T18:46:33Z |
| format | Article |
| id | doaj.art-aa5b34217f1c41658cc6b2acc00741d0 |
| institution | Directory Open Access Journal |
| issn | 1477-3155 |
| language | English |
| last_indexed | 2024-04-11T18:46:33Z |
| publishDate | 2021-07-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Nanobiotechnology |
| spelling | doaj.art-aa5b34217f1c41658cc6b2acc00741d02022-12-22T04:08:48ZengBMCJournal of Nanobiotechnology1477-31552021-07-0119112310.1186/s12951-021-00947-9Amplified antitumor efficacy by a targeted drug retention and chemosensitization strategy-based “combo” nanoagent together with PD-L1 blockade in reversing multidrug resistanceWeixi Jiang0Lei Su1Meng Ao2Xun Guo3Chen Cheng4Yuanli Luo5Zhuoyan Xie6Xingyue Wang7Junrui Wang8Shuling Liu9Yang Cao10Pan Li11Zhigang Wang12Haitao Ran13Zhiyi Zhou14Jianli Ren15Department of Ultrasound, Chongqing Key Laboratory of Ultrasound Molecular Imaging, The Second Affiliated Hospital of Chongqing Medical UniversityDepartment of Ultrasound, Chongqing Key Laboratory of Ultrasound Molecular Imaging, The Second Affiliated Hospital of Chongqing Medical UniversityDepartment of Ultrasound, Chongqing Key Laboratory of Ultrasound Molecular Imaging, The Second Affiliated Hospital of Chongqing Medical UniversityDepartment of Ultrasound, Chongqing Key Laboratory of Ultrasound Molecular Imaging, The Second Affiliated Hospital of Chongqing Medical UniversityDepartment of Ultrasound, Chongqing Key Laboratory of Ultrasound Molecular Imaging, The Second Affiliated Hospital of Chongqing Medical UniversityDepartment of Ultrasound, Chongqing Key Laboratory of Ultrasound Molecular Imaging, The Second Affiliated Hospital of Chongqing Medical UniversityDepartment of Ultrasound, Chongqing Key Laboratory of Ultrasound Molecular Imaging, The Second Affiliated Hospital of Chongqing Medical UniversityDepartment of Ultrasound, Chongqing Key Laboratory of Ultrasound Molecular Imaging, The Second Affiliated Hospital of Chongqing Medical UniversityDepartment of Ultrasound, Chongqing Key Laboratory of Ultrasound Molecular Imaging, The Second Affiliated Hospital of Chongqing Medical UniversityDepartment of Radiology, The Second Affiliated Hospital of Chongqing Medical UniversityDepartment of Ultrasound, Chongqing Key Laboratory of Ultrasound Molecular Imaging, The Second Affiliated Hospital of Chongqing Medical UniversityDepartment of Ultrasound, Chongqing Key Laboratory of Ultrasound Molecular Imaging, The Second Affiliated Hospital of Chongqing Medical UniversityDepartment of Ultrasound, Chongqing Key Laboratory of Ultrasound Molecular Imaging, The Second Affiliated Hospital of Chongqing Medical UniversityDepartment of Ultrasound, Chongqing Key Laboratory of Ultrasound Molecular Imaging, The Second Affiliated Hospital of Chongqing Medical UniversityDepartment of General Practice of Chongqing General Hospital, University of Chinese Academy of SciencesDepartment of Ultrasound, Chongqing Key Laboratory of Ultrasound Molecular Imaging, The Second Affiliated Hospital of Chongqing Medical UniversityAbstract Background Recent studies have demonstrated that multidrug resistance (MDR) is a critical factor in the low efficacy of cancer chemotherapy. The main mechanism of MDR arises from the overexpression of P-glycoprotein (P-gp), which actively enhances drug efflux and limits the effectiveness of chemotherapeutic agents. Results In this study, we fabricated a “combo” nanoagent equipping with triple synergistic strategies for enhancing antitumor efficacy against MDR cells. Tumor homing-penetrating peptide endows the nanosystem with targeting and penetrating capabilities in the first stage of tumor internalization. The abundant amine groups of polyethylenimine (PEI)-modified nanoparticles then trigger a proton sponge effect to promote endo/lysosomal escape, which enhances the intracellular accumulation and retention of anticancer drugs. Furthermore, copper tetrakis(4-carboxyphenyl)porphyrin (CuTCPP) encapsulated in the nanosystem, effectively scavenges endogenous glutathione (GSH) to reduce the detoxification mediated by GSH and sensitize the cancer cells to drugs, while simultaneously serving as a photoacoustic imaging (PAI) contrast agent for image visualization. Moreover, we also verify that these versatile nanoparticles in combination with PD-1/PD-L1 blockade therapy can not only activate immunological responses but also inhibit P-gp expression to obliterate primary and metastatic tumors. Conclusion This work shows a significant enhancement in therapeutic efficacy against MDR cells and syngeneic tumors by using multiple MDR reversing strategies compared to an equivalent dose of free paclitaxel. Graphic Abstracthttps://doi.org/10.1186/s12951-021-00947-9Multidrug resistanceEndo/lysosomal escapeTumor homing-penetrating peptideChemotherapy enhancementPD-L1 blockade |
| spellingShingle | Weixi Jiang Lei Su Meng Ao Xun Guo Chen Cheng Yuanli Luo Zhuoyan Xie Xingyue Wang Junrui Wang Shuling Liu Yang Cao Pan Li Zhigang Wang Haitao Ran Zhiyi Zhou Jianli Ren Amplified antitumor efficacy by a targeted drug retention and chemosensitization strategy-based “combo” nanoagent together with PD-L1 blockade in reversing multidrug resistance Journal of Nanobiotechnology Multidrug resistance Endo/lysosomal escape Tumor homing-penetrating peptide Chemotherapy enhancement PD-L1 blockade |
| title | Amplified antitumor efficacy by a targeted drug retention and chemosensitization strategy-based “combo” nanoagent together with PD-L1 blockade in reversing multidrug resistance |
| title_full | Amplified antitumor efficacy by a targeted drug retention and chemosensitization strategy-based “combo” nanoagent together with PD-L1 blockade in reversing multidrug resistance |
| title_fullStr | Amplified antitumor efficacy by a targeted drug retention and chemosensitization strategy-based “combo” nanoagent together with PD-L1 blockade in reversing multidrug resistance |
| title_full_unstemmed | Amplified antitumor efficacy by a targeted drug retention and chemosensitization strategy-based “combo” nanoagent together with PD-L1 blockade in reversing multidrug resistance |
| title_short | Amplified antitumor efficacy by a targeted drug retention and chemosensitization strategy-based “combo” nanoagent together with PD-L1 blockade in reversing multidrug resistance |
| title_sort | amplified antitumor efficacy by a targeted drug retention and chemosensitization strategy based combo nanoagent together with pd l1 blockade in reversing multidrug resistance |
| topic | Multidrug resistance Endo/lysosomal escape Tumor homing-penetrating peptide Chemotherapy enhancement PD-L1 blockade |
| url | https://doi.org/10.1186/s12951-021-00947-9 |
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