GGT and GSH-triggered nanoplatform for efficient gambogic acid delivery and tumor penetration in triple-negative breast cancer
Emerging nanodrug delivery strategies seek to overcome tumor heterogeneity and enhance drug penetration in the dense matrix of solid tumors. This study presents a dual-responsive nanoplatform, poly(lactic-co-glycolic acid)-disulfide-polyethylene glycol-glutamate (PLGA-SS-PEG-Glu) loaded with Gambogi...
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Elsevier
2025-08-01
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| Series: | Materials Today Bio |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2590006425006003 |
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| author | Su Li Qinghua Wang Chen Su Zhen Jia Guoshuang Shen Mengting Da Rui Yang Jiuda Zhao Daozhen Chen |
| author_facet | Su Li Qinghua Wang Chen Su Zhen Jia Guoshuang Shen Mengting Da Rui Yang Jiuda Zhao Daozhen Chen |
| author_sort | Su Li |
| collection | DOAJ |
| description | Emerging nanodrug delivery strategies seek to overcome tumor heterogeneity and enhance drug penetration in the dense matrix of solid tumors. This study presents a dual-responsive nanoplatform, poly(lactic-co-glycolic acid)-disulfide-polyethylene glycol-glutamate (PLGA-SS-PEG-Glu) loaded with Gambogic acid (GA), engineered to exploit γ-glutamyltranspeptidase (GGT) and glutathione (GSH) triggers specific to the triple-negative breast cancer (TNBC) microenvironment. Designed with Boc-L-Glutamic Acid-1-tert-butyl ester (Boc-Glu-OtBu), this nanoplatform achieves enzyme-triggered charge reversal to enhance tumor penetration, facilitating GGT-induced charge-switching and GSH-responsive GA release. In vitro, PLGA-SS-PEG-Glu@GA shows potent cytotoxicity (IC50 = 0.80 μg/ml) against 4T1 TNBC cells, inducing apoptosis and inhibiting cell proliferation through energy-dependent, GGT-mediated endocytosis. Compensatory Nrf2/HO-1 activation mechanistically induced by GA-loaded nanoplatform ultimately potentiated mitochondrial apoptotic pathway (Bcl-2/caspase-3) initiation, promoting apoptosis. In vivo, this nanoplatform leveraged its tumor-specific enzymatic and redox microenvironment-responsive properties to achieve enhanced deep intratumoral penetration. Treatment for 2 weeks effectively suppressed primary tumor growth, while extended therapy to one month significantly inhibited the formation of pulmonary metastatic foci. This dual-responsive strategy not only elevates drug bioavailability at the tumor site but also provides a promising solution to overcome critical barriers in solid tumor drug delivery. |
| format | Article |
| id | doaj-art-bfe5a3e09c5e44f59d297c910585724e |
| institution | DOAJ |
| issn | 2590-0064 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Materials Today Bio |
| spelling | doaj-art-bfe5a3e09c5e44f59d297c910585724e2025-08-20T03:15:54ZengElsevierMaterials Today Bio2590-00642025-08-013310203010.1016/j.mtbio.2025.102030GGT and GSH-triggered nanoplatform for efficient gambogic acid delivery and tumor penetration in triple-negative breast cancerSu Li0Qinghua Wang1Chen Su2Zhen Jia3Guoshuang Shen4Mengting Da5Rui Yang6Jiuda Zhao7Daozhen Chen8Wuxi Maternal and Child Health Hospital, Wuxi School of Medicine, Jiangnan University, Jiangsu, 214002, PR ChinaWuxi Maternal and Child Health Hospital, Wuxi School of Medicine, Jiangnan University, Jiangsu, 214002, PR ChinaWuxi Maternal and Child Health Hospital, Wuxi School of Medicine, Jiangnan University, Jiangsu, 214002, PR ChinaDepartment of Obstetrics and Gynecology, Haidong No. 2 People's Hospital, Haidong, 810699, PR ChinaBreast Disease Diagnosis and Treatment Center, Affiliated Hospital of Qinghai University, Affiliated Cancer Hospital of Qinghai University, Xining, 810000, PR ChinaBreast Disease Diagnosis and Treatment Center, Affiliated Hospital of Qinghai University, Affiliated Cancer Hospital of Qinghai University, Xining, 810000, PR ChinaWuxi Maternal and Child Health Hospital, Wuxi School of Medicine, Jiangnan University, Jiangsu, 214002, PR China; Corresponding author.Breast Disease Diagnosis and Treatment Center, Affiliated Hospital of Qinghai University, Affiliated Cancer Hospital of Qinghai University, Xining, 810000, PR China; Corresponding author.Wuxi Maternal and Child Health Hospital, Wuxi School of Medicine, Jiangnan University, Jiangsu, 214002, PR China; Department of Obstetrics and Gynecology, Haidong No. 2 People's Hospital, Haidong, 810699, PR China; Corresponding author. Wuxi Maternal and Child Health Hospital, Wuxi School of Medicine, Jiangnan University, Jiangsu, 214002, PR China.Emerging nanodrug delivery strategies seek to overcome tumor heterogeneity and enhance drug penetration in the dense matrix of solid tumors. This study presents a dual-responsive nanoplatform, poly(lactic-co-glycolic acid)-disulfide-polyethylene glycol-glutamate (PLGA-SS-PEG-Glu) loaded with Gambogic acid (GA), engineered to exploit γ-glutamyltranspeptidase (GGT) and glutathione (GSH) triggers specific to the triple-negative breast cancer (TNBC) microenvironment. Designed with Boc-L-Glutamic Acid-1-tert-butyl ester (Boc-Glu-OtBu), this nanoplatform achieves enzyme-triggered charge reversal to enhance tumor penetration, facilitating GGT-induced charge-switching and GSH-responsive GA release. In vitro, PLGA-SS-PEG-Glu@GA shows potent cytotoxicity (IC50 = 0.80 μg/ml) against 4T1 TNBC cells, inducing apoptosis and inhibiting cell proliferation through energy-dependent, GGT-mediated endocytosis. Compensatory Nrf2/HO-1 activation mechanistically induced by GA-loaded nanoplatform ultimately potentiated mitochondrial apoptotic pathway (Bcl-2/caspase-3) initiation, promoting apoptosis. In vivo, this nanoplatform leveraged its tumor-specific enzymatic and redox microenvironment-responsive properties to achieve enhanced deep intratumoral penetration. Treatment for 2 weeks effectively suppressed primary tumor growth, while extended therapy to one month significantly inhibited the formation of pulmonary metastatic foci. This dual-responsive strategy not only elevates drug bioavailability at the tumor site but also provides a promising solution to overcome critical barriers in solid tumor drug delivery.http://www.sciencedirect.com/science/article/pii/S2590006425006003γ-glutamyltranspeptidaseTriple-negative breast cancerDual-responsiveCharge-reversalCancer therapy |
| spellingShingle | Su Li Qinghua Wang Chen Su Zhen Jia Guoshuang Shen Mengting Da Rui Yang Jiuda Zhao Daozhen Chen GGT and GSH-triggered nanoplatform for efficient gambogic acid delivery and tumor penetration in triple-negative breast cancer Materials Today Bio γ-glutamyltranspeptidase Triple-negative breast cancer Dual-responsive Charge-reversal Cancer therapy |
| title | GGT and GSH-triggered nanoplatform for efficient gambogic acid delivery and tumor penetration in triple-negative breast cancer |
| title_full | GGT and GSH-triggered nanoplatform for efficient gambogic acid delivery and tumor penetration in triple-negative breast cancer |
| title_fullStr | GGT and GSH-triggered nanoplatform for efficient gambogic acid delivery and tumor penetration in triple-negative breast cancer |
| title_full_unstemmed | GGT and GSH-triggered nanoplatform for efficient gambogic acid delivery and tumor penetration in triple-negative breast cancer |
| title_short | GGT and GSH-triggered nanoplatform for efficient gambogic acid delivery and tumor penetration in triple-negative breast cancer |
| title_sort | ggt and gsh triggered nanoplatform for efficient gambogic acid delivery and tumor penetration in triple negative breast cancer |
| topic | γ-glutamyltranspeptidase Triple-negative breast cancer Dual-responsive Charge-reversal Cancer therapy |
| url | http://www.sciencedirect.com/science/article/pii/S2590006425006003 |
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