Amphiphilic cationic triblock polymers for p53-mediated triple-negative breast cancer gene therapy
Polycationic vectors are a promising class of gene delivery systems. To improve delivery efficiency and reduce cytotoxicity, hydrophobic modification has been proposed as an effective way. Herein, we synthesized a class of terpolymer vectors with various hydrophobicities as well as multiple biodegra...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2022-07-01
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| Series: | Materials & Design |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S026412752200380X |
| _version_ | 1811235591575044096 |
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| author | Hui Liu Xiaoyun Zhao Yu Bai Huichao Xie Zhen Yang Yichen Wang Yongfeng Chen Yucen Luo Mengrui Ma Wenwen Lu Jizhuang Ma Tianzhi Yang Bo Jin Pingtian Ding |
| author_facet | Hui Liu Xiaoyun Zhao Yu Bai Huichao Xie Zhen Yang Yichen Wang Yongfeng Chen Yucen Luo Mengrui Ma Wenwen Lu Jizhuang Ma Tianzhi Yang Bo Jin Pingtian Ding |
| author_sort | Hui Liu |
| collection | DOAJ |
| description | Polycationic vectors are a promising class of gene delivery systems. To improve delivery efficiency and reduce cytotoxicity, hydrophobic modification has been proposed as an effective way. Herein, we synthesized a class of terpolymer vectors with various hydrophobicities as well as multiple biodegradable disulfide bonds and cationic side chains. The chemical structure and hydrophobic modification ratio of polymers were characterized. The amphiphilic vectors were able to condense pDNA to form flexible and uniform nanoparticles with a size of 60–85 nm. The shielding effect of hydrophobic side chains led to a lower zeta potential and reduced cytotoxicity. The endocytosis efficiency of amphiphilic vectors was significantly increased and the endocytosis pathway shifted from mainly via the clathrin pathway to clathrin/caveolae/lipid raft co-mediated endocytosis. The amphiphilic vectors demonstrated significantly higher transfection efficiency. In addition, the hydrophobic structural domain of polymers could improve serum stability, alleviating the serum inhibition commonly seen in cationic polymers. Then, we tested the tumor-suppressor gene wtp53 delivered by the amphiphilic vectors in triple-negative breast cancer models both in vitro and in vivo. Tumor cell cycle arrest and apoptosis were triggered through the regulation of downstream cell cycle proteins and apoptosis proteins, inhibiting tumor growth with an excellent safety profile. |
| first_indexed | 2024-04-12T11:54:34Z |
| format | Article |
| id | doaj.art-3bd7609fde754f3a9614ef614e910551 |
| institution | Directory Open Access Journal |
| issn | 0264-1275 |
| language | English |
| last_indexed | 2024-04-12T11:54:34Z |
| publishDate | 2022-07-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Materials & Design |
| spelling | doaj.art-3bd7609fde754f3a9614ef614e9105512022-12-22T03:34:02ZengElsevierMaterials & Design0264-12752022-07-01219110758Amphiphilic cationic triblock polymers for p53-mediated triple-negative breast cancer gene therapyHui Liu0Xiaoyun Zhao1Yu Bai2Huichao Xie3Zhen Yang4Yichen Wang5Yongfeng Chen6Yucen Luo7Mengrui Ma8Wenwen Lu9Jizhuang Ma10Tianzhi Yang11Bo Jin12Pingtian Ding13School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, ChinaSchool of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang 110016, ChinaSchool of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, ChinaSchool of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, ChinaResearch and Development Center, CR Sanjiu Medical & Pharmaceutical Co., Ltd., Shenzhen 518110, ChinaSchool of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, ChinaSchool of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, ChinaSchool of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, ChinaSchool of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, ChinaSchool of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, ChinaSchool of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, ChinaDepartment of Pharmaceutical Sciences, School of Pharmacy, Husson University, Bangor 04401-2929, ME, USADepartment of Medical Oncology, The First Hospital of China Medical University, Shenyang 110001, China; Corresponding authors at: School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, China (P.T. Ding).School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, China; College of Pharmacy, Shenzhen Technology University, Shenzhen 518118, China; Corresponding authors at: School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, China (P.T. Ding).Polycationic vectors are a promising class of gene delivery systems. To improve delivery efficiency and reduce cytotoxicity, hydrophobic modification has been proposed as an effective way. Herein, we synthesized a class of terpolymer vectors with various hydrophobicities as well as multiple biodegradable disulfide bonds and cationic side chains. The chemical structure and hydrophobic modification ratio of polymers were characterized. The amphiphilic vectors were able to condense pDNA to form flexible and uniform nanoparticles with a size of 60–85 nm. The shielding effect of hydrophobic side chains led to a lower zeta potential and reduced cytotoxicity. The endocytosis efficiency of amphiphilic vectors was significantly increased and the endocytosis pathway shifted from mainly via the clathrin pathway to clathrin/caveolae/lipid raft co-mediated endocytosis. The amphiphilic vectors demonstrated significantly higher transfection efficiency. In addition, the hydrophobic structural domain of polymers could improve serum stability, alleviating the serum inhibition commonly seen in cationic polymers. Then, we tested the tumor-suppressor gene wtp53 delivered by the amphiphilic vectors in triple-negative breast cancer models both in vitro and in vivo. Tumor cell cycle arrest and apoptosis were triggered through the regulation of downstream cell cycle proteins and apoptosis proteins, inhibiting tumor growth with an excellent safety profile.http://www.sciencedirect.com/science/article/pii/S026412752200380XGene therapyCationic polymerHydrophilic-hydrophobic balanceWtp53Transfection efficiencyTumor growth suppression |
| spellingShingle | Hui Liu Xiaoyun Zhao Yu Bai Huichao Xie Zhen Yang Yichen Wang Yongfeng Chen Yucen Luo Mengrui Ma Wenwen Lu Jizhuang Ma Tianzhi Yang Bo Jin Pingtian Ding Amphiphilic cationic triblock polymers for p53-mediated triple-negative breast cancer gene therapy Materials & Design Gene therapy Cationic polymer Hydrophilic-hydrophobic balance Wtp53 Transfection efficiency Tumor growth suppression |
| title | Amphiphilic cationic triblock polymers for p53-mediated triple-negative breast cancer gene therapy |
| title_full | Amphiphilic cationic triblock polymers for p53-mediated triple-negative breast cancer gene therapy |
| title_fullStr | Amphiphilic cationic triblock polymers for p53-mediated triple-negative breast cancer gene therapy |
| title_full_unstemmed | Amphiphilic cationic triblock polymers for p53-mediated triple-negative breast cancer gene therapy |
| title_short | Amphiphilic cationic triblock polymers for p53-mediated triple-negative breast cancer gene therapy |
| title_sort | amphiphilic cationic triblock polymers for p53 mediated triple negative breast cancer gene therapy |
| topic | Gene therapy Cationic polymer Hydrophilic-hydrophobic balance Wtp53 Transfection efficiency Tumor growth suppression |
| url | http://www.sciencedirect.com/science/article/pii/S026412752200380X |
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