GSH-activable heterotrimeric nano-prodrug for precise synergistic therapy of TNBC
Combination chemotherapy is an effective approach for triple-negative breast cancer (TNBC) therapy, especially when drugs are administered at specific optimal ratios. However, at present, strategies involving precise and controllable ratios based on effective loading and release of drugs are unavail...
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| Format: | Article |
| Language: | English |
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Elsevier
2024-04-01
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| Series: | Biomedicine & Pharmacotherapy |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0753332224002592 |
| _version_ | 1797248403481034752 |
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| author | Xiaojing Zhang Yansong Chen Jingwei Tang Chen Chen Yanfeng Sun Hao Zhang Mengxiang Qiao Gongsheng Jin Xianfu Liu |
| author_facet | Xiaojing Zhang Yansong Chen Jingwei Tang Chen Chen Yanfeng Sun Hao Zhang Mengxiang Qiao Gongsheng Jin Xianfu Liu |
| author_sort | Xiaojing Zhang |
| collection | DOAJ |
| description | Combination chemotherapy is an effective approach for triple-negative breast cancer (TNBC) therapy, especially when drugs are administered at specific optimal ratios. However, at present, strategies involving precise and controllable ratios based on effective loading and release of drugs are unavailable. Herein, we designed and synthesized a glutathione (GSH)--responsive heterotrimeric prodrug and formulated it with an amphiphilic polymer to obtain nanoparticles (DSSC2 NPs) for precise synergistic chemotherapy of TNBC. The heterotrimeric prodrug was prepared using docetaxel (DTX) and curcumin (CUR) at the optimal synergistic ratio of 1: 2. DTX and CUR were covalently conjugated by disulfide linkers. Compared with control NPs, DSSC2 NPs had quantitative/ratiometric drug loading, high drug co-loading capacity, better colloidal stability, and less premature drug leakage. After systemic administration, DSSC2 NPs selectively accumulated in tumor tissues and released the encapsulated drugs triggered by high levels of GSH in cancer cells. In vitro and in vivo experiments validated that DSSC2 NPs released DTX and CUR at the predefined ratio and had a highly synergistic therapeutic effect on tumor suppression in TNBC, which can be attributed to ratiometric drug delivery and synchronous drug activation. Altogether, the heterotrimeric prodrug delivery system developed in this study represents an effective and novel approach for combination chemotherapy. |
| first_indexed | 2024-04-24T20:14:02Z |
| format | Article |
| id | doaj.art-417d310ab9a8470f89258ff4a7f0caad |
| institution | Directory Open Access Journal |
| issn | 0753-3322 |
| language | English |
| last_indexed | 2024-04-24T20:14:02Z |
| publishDate | 2024-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Biomedicine & Pharmacotherapy |
| spelling | doaj.art-417d310ab9a8470f89258ff4a7f0caad2024-03-23T06:22:55ZengElsevierBiomedicine & Pharmacotherapy0753-33222024-04-01173116375GSH-activable heterotrimeric nano-prodrug for precise synergistic therapy of TNBCXiaojing Zhang0Yansong Chen1Jingwei Tang2Chen Chen3Yanfeng Sun4Hao Zhang5Mengxiang Qiao6Gongsheng Jin7Xianfu Liu8Department of Surgical Oncology, The First Affiliated Hospital of Bengbu Medical University, Bengbu 233004, ChinaDepartment of Surgical Oncology, The First Affiliated Hospital of Bengbu Medical University, Bengbu 233004, ChinaDepartment of Surgical Oncology, The First Affiliated Hospital of Bengbu Medical University, Bengbu 233004, ChinaDepartment of Surgical Oncology, The First Affiliated Hospital of Bengbu Medical University, Bengbu 233004, ChinaDepartment of Surgical Oncology, The First Affiliated Hospital of Bengbu Medical University, Bengbu 233004, ChinaDepartment of Surgical Oncology, The First Affiliated Hospital of Bengbu Medical University, Bengbu 233004, ChinaDepartment of Surgical Oncology, The First Affiliated Hospital of Bengbu Medical University, Bengbu 233004, ChinaCorresponding authors.; Department of Surgical Oncology, The First Affiliated Hospital of Bengbu Medical University, Bengbu 233004, ChinaCorresponding authors.; Department of Surgical Oncology, The First Affiliated Hospital of Bengbu Medical University, Bengbu 233004, ChinaCombination chemotherapy is an effective approach for triple-negative breast cancer (TNBC) therapy, especially when drugs are administered at specific optimal ratios. However, at present, strategies involving precise and controllable ratios based on effective loading and release of drugs are unavailable. Herein, we designed and synthesized a glutathione (GSH)--responsive heterotrimeric prodrug and formulated it with an amphiphilic polymer to obtain nanoparticles (DSSC2 NPs) for precise synergistic chemotherapy of TNBC. The heterotrimeric prodrug was prepared using docetaxel (DTX) and curcumin (CUR) at the optimal synergistic ratio of 1: 2. DTX and CUR were covalently conjugated by disulfide linkers. Compared with control NPs, DSSC2 NPs had quantitative/ratiometric drug loading, high drug co-loading capacity, better colloidal stability, and less premature drug leakage. After systemic administration, DSSC2 NPs selectively accumulated in tumor tissues and released the encapsulated drugs triggered by high levels of GSH in cancer cells. In vitro and in vivo experiments validated that DSSC2 NPs released DTX and CUR at the predefined ratio and had a highly synergistic therapeutic effect on tumor suppression in TNBC, which can be attributed to ratiometric drug delivery and synchronous drug activation. Altogether, the heterotrimeric prodrug delivery system developed in this study represents an effective and novel approach for combination chemotherapy.http://www.sciencedirect.com/science/article/pii/S0753332224002592Ratiometric drug loadingCombination therapyGSH-responsiveConstant drug ratioTumor active targeting |
| spellingShingle | Xiaojing Zhang Yansong Chen Jingwei Tang Chen Chen Yanfeng Sun Hao Zhang Mengxiang Qiao Gongsheng Jin Xianfu Liu GSH-activable heterotrimeric nano-prodrug for precise synergistic therapy of TNBC Biomedicine & Pharmacotherapy Ratiometric drug loading Combination therapy GSH-responsive Constant drug ratio Tumor active targeting |
| title | GSH-activable heterotrimeric nano-prodrug for precise synergistic therapy of TNBC |
| title_full | GSH-activable heterotrimeric nano-prodrug for precise synergistic therapy of TNBC |
| title_fullStr | GSH-activable heterotrimeric nano-prodrug for precise synergistic therapy of TNBC |
| title_full_unstemmed | GSH-activable heterotrimeric nano-prodrug for precise synergistic therapy of TNBC |
| title_short | GSH-activable heterotrimeric nano-prodrug for precise synergistic therapy of TNBC |
| title_sort | gsh activable heterotrimeric nano prodrug for precise synergistic therapy of tnbc |
| topic | Ratiometric drug loading Combination therapy GSH-responsive Constant drug ratio Tumor active targeting |
| url | http://www.sciencedirect.com/science/article/pii/S0753332224002592 |
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