Small‐molecule nanoprodrug with high drug loading and EGFR, PI3K/AKT dual‐inhibiting properties for bladder cancer treatment
Bladder cancer (BCa) is one of the most common malignancies worldwide. Although multiple efforts have been made, the 5‐year survival rate of patients with BCa remains unchanged in recent years. Overexpression of the epidermal growth factor receptor (EGFR) is found in ≈74% of BCa tissue specimens; ho...
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| Published in | Exploration (Beijing, China) Vol. 3; no. 5; pp. 20220141 - n/a |
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| Main Authors | , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
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China
John Wiley & Sons, Inc
01.10.2023
Wiley |
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| Abstract | Bladder cancer (BCa) is one of the most common malignancies worldwide. Although multiple efforts have been made, the 5‐year survival rate of patients with BCa remains unchanged in recent years. Overexpression of the epidermal growth factor receptor (EGFR) is found in ≈74% of BCa tissue specimens; however, current EGFR‐based targeted therapies show little benefit for BCa patients, as the EGFR downstream pathways appear to be circumvented by other receptor tyrosine kinases (RTKs). In this study, two natural products are identified, namely triptolide (TPL) and hesperidin (HSP), that target and inhibit the EGFR and its downstream PI3K/AKT pathway in BCa. To synergistically combine triptolide and hesperidin, a succinic acid linker was employed to conjugate them and formed an amphiphilic TPL‐HSP EGFR‐targeting prodrug (THE), which further self‐assembled to generate nanoparticles (THE NPs). These NPs allowed the EGFR‐targeted delivery of the triptolide and hesperidin, and simultaneous inhibition of the EGFR and PI3K/AKT both in vitro and in vivo. This study provides a promising EGFR‐targeted delivery approach with the dual inhibition of the EGFR and PI3K/AKT, while also exhibiting a high drug loading and low toxicity. Our formulation may be a suitable option to deliver natural products for BCa treatment by EGFR‐targeted therapy. |
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| AbstractList | Abstract Bladder cancer (BCa) is one of the most common malignancies worldwide. Although multiple efforts have been made, the 5‐year survival rate of patients with BCa remains unchanged in recent years. Overexpression of the epidermal growth factor receptor (EGFR) is found in ≈74% of BCa tissue specimens; however, current EGFR‐based targeted therapies show little benefit for BCa patients, as the EGFR downstream pathways appear to be circumvented by other receptor tyrosine kinases (RTKs). In this study, two natural products are identified, namely triptolide (TPL) and hesperidin (HSP), that target and inhibit the EGFR and its downstream PI3K/AKT pathway in BCa. To synergistically combine triptolide and hesperidin, a succinic acid linker was employed to conjugate them and formed an amphiphilic TPL‐HSP EGFR‐targeting prodrug (THE), which further self‐assembled to generate nanoparticles (THE NPs). These NPs allowed the EGFR‐targeted delivery of the triptolide and hesperidin, and simultaneous inhibition of the EGFR and PI3K/AKT both in vitro and in vivo. This study provides a promising EGFR‐targeted delivery approach with the dual inhibition of the EGFR and PI3K/AKT, while also exhibiting a high drug loading and low toxicity. Our formulation may be a suitable option to deliver natural products for BCa treatment by EGFR‐targeted therapy. Bladder cancer (BCa) is one of the most common malignancies worldwide. Although multiple efforts have been made, the 5-year survival rate of patients with BCa remains unchanged in recent years. Overexpression of the epidermal growth factor receptor (EGFR) is found in ≈74% of BCa tissue specimens; however, current EGFR-based targeted therapies show little benefit for BCa patients, as the EGFR downstream pathways appear to be circumvented by other receptor tyrosine kinases (RTKs). In this study, two natural products are identified, namely triptolide (TPL) and hesperidin (HSP), that target and inhibit the EGFR and its downstream PI3K/AKT pathway in BCa. To synergistically combine triptolide and hesperidin, a succinic acid linker was employed to conjugate them and formed an amphiphilic TPL-HSP EGFR-targeting prodrug (THE), which further self-assembled to generate nanoparticles (THE NPs). These NPs allowed the EGFR-targeted delivery of the triptolide and hesperidin, and simultaneous inhibition of the EGFR and PI3K/AKT both in vitro and in vivo. This study provides a promising EGFR-targeted delivery approach with the dual inhibition of the EGFR and PI3K/AKT, while also exhibiting a high drug loading and low toxicity. Our formulation may be a suitable option to deliver natural products for BCa treatment by EGFR-targeted therapy. Bladder cancer (BCa) is one of the most common malignancies worldwide. Although multiple efforts have been made, the 5-year survival rate of patients with BCa remains unchanged in recent years. Overexpression of the epidermal growth factor receptor (EGFR) is found in ≈74% of BCa tissue specimens; however, current EGFR-based targeted therapies show little benefit for BCa patients, as the EGFR downstream pathways appear to be circumvented by other receptor tyrosine kinases (RTKs). In this study, two natural products are identified, namely triptolide (TPL) and hesperidin (HSP), that target and inhibit the EGFR and its downstream PI3K/AKT pathway in BCa. To synergistically combine triptolide and hesperidin, a succinic acid linker was employed to conjugate them and formed an amphiphilic TPL-HSP EGFR-targeting prodrug (THE), which further self-assembled to generate nanoparticles (THE NPs). These NPs allowed the EGFR-targeted delivery of the triptolide and hesperidin, and simultaneous inhibition of the EGFR and PI3K/AKT both in vitro and in vivo. This study provides a promising EGFR-targeted delivery approach with the dual inhibition of the EGFR and PI3K/AKT, while also exhibiting a high drug loading and low toxicity. Our formulation may be a suitable option to deliver natural products for BCa treatment by EGFR-targeted therapy.Bladder cancer (BCa) is one of the most common malignancies worldwide. Although multiple efforts have been made, the 5-year survival rate of patients with BCa remains unchanged in recent years. Overexpression of the epidermal growth factor receptor (EGFR) is found in ≈74% of BCa tissue specimens; however, current EGFR-based targeted therapies show little benefit for BCa patients, as the EGFR downstream pathways appear to be circumvented by other receptor tyrosine kinases (RTKs). In this study, two natural products are identified, namely triptolide (TPL) and hesperidin (HSP), that target and inhibit the EGFR and its downstream PI3K/AKT pathway in BCa. To synergistically combine triptolide and hesperidin, a succinic acid linker was employed to conjugate them and formed an amphiphilic TPL-HSP EGFR-targeting prodrug (THE), which further self-assembled to generate nanoparticles (THE NPs). These NPs allowed the EGFR-targeted delivery of the triptolide and hesperidin, and simultaneous inhibition of the EGFR and PI3K/AKT both in vitro and in vivo. This study provides a promising EGFR-targeted delivery approach with the dual inhibition of the EGFR and PI3K/AKT, while also exhibiting a high drug loading and low toxicity. Our formulation may be a suitable option to deliver natural products for BCa treatment by EGFR-targeted therapy. |
| Author | Jin, Haibao Luo, Lianxiang Song, Zewen Wu, Hao Qu, Haijing Wei, Di Li, Guoyin Yang, Wei Zhu, Zheng Zhou, Gang Zhang, Jing Xue, Xiangdong Ru, Yi Bao, Xuanwen Yan, Zhao |
| Author_xml | – sequence: 1 givenname: Guoyin surname: Li fullname: Li, Guoyin organization: College of Life Science and Agronomy Zhoukou Normal University Zhoukou Henan China, Department of Biochemistry and Molecular Biology State Key Laboratory of Cancer Biology The Fourth Military Medical University Xi'an Shaanxi China – sequence: 2 givenname: Zewen surname: Song fullname: Song, Zewen organization: Department of Oncology Central South University Third Xiangya Hospital Changsha Hunan China – sequence: 3 givenname: Yi surname: Ru fullname: Ru, Yi organization: Department of Biochemistry and Molecular Biology State Key Laboratory of Cancer Biology The Fourth Military Medical University Xi'an Shaanxi China – sequence: 4 givenname: Jing surname: Zhang fullname: Zhang, Jing organization: Department of Pathology Xijing Hospital State Key Laboratory of Cancer Biology The Fourth Military Medical University Xi'an Shaanxi China – sequence: 5 givenname: Lianxiang surname: Luo fullname: Luo, Lianxiang organization: The Marine Biomedical Research Institute Guangdong Medical University Zhanjiang Guangdong China – sequence: 6 givenname: Wei surname: Yang fullname: Yang, Wei organization: Warshel Institute for Computational Biology School of Science and Engineering The Chinese University of Hong Kong Shenzhen China – sequence: 7 givenname: Hao orcidid: 0000-0003-1262-5932 surname: Wu fullname: Wu, Hao organization: School of Basic Medical Sciences Xi'an Key Laboratory of Immune Related Diseases Xi'an Jiaotong University Xi'an Shaanxi China – sequence: 8 givenname: Haibao surname: Jin fullname: Jin, Haibao organization: Shanghai Key Laboratory of Advanced Polymeric Materials School of Materials Science and Engineering East China University of Science and Technology Shanghai China – sequence: 9 givenname: Xuanwen surname: Bao fullname: Bao, Xuanwen organization: Department of Medical Oncology The First Affiliated Hospital College of Medicine Zhejiang University Hangzhou Zhejiang China – sequence: 10 givenname: Di surname: Wei fullname: Wei, Di organization: Graduate School Department of Biochemistry and Molecular Biology The Fourth Military Medical University Xi'an Shaanxi China – sequence: 11 givenname: Zhao surname: Yan fullname: Yan, Zhao organization: Graduate School Department of Biochemistry and Molecular Biology The Fourth Military Medical University Xi'an Shaanxi China – sequence: 12 givenname: Haijing surname: Qu fullname: Qu, Haijing organization: School of Pharmacy Shanghai Jiao Tong University Xi'an Shanghai China – sequence: 13 givenname: Zheng surname: Zhu fullname: Zhu, Zheng organization: Department of Medicine Harvard Medical School Boston Massachusetts USA – sequence: 14 givenname: Xiangdong surname: Xue fullname: Xue, Xiangdong organization: School of Pharmacy Shanghai Jiao Tong University Xi'an Shanghai China – sequence: 15 givenname: Gang orcidid: 0000-0001-8258-0923 surname: Zhou fullname: Zhou, Gang organization: National Translational Science Center for Molecular Medicine Department of Cell Biology State Key Laboratory of Cancer Biology Fourth Military Medical University Xi'an Shaanxi China |
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| Copyright | 2023 The Authors. Exploration published by Henan University and John Wiley & Sons Australia, Ltd. 2023. This work is published under http://creativecommons.org/licenses/by/4.0/ (the "License"). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License. |
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| Snippet | Bladder cancer (BCa) is one of the most common malignancies worldwide. Although multiple efforts have been made, the 5‐year survival rate of patients with BCa... Bladder cancer (BCa) is one of the most common malignancies worldwide. Although multiple efforts have been made, the 5-year survival rate of patients with BCa... Abstract Bladder cancer (BCa) is one of the most common malignancies worldwide. Although multiple efforts have been made, the 5‐year survival rate of patients... |
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| SubjectTerms | 1-Phosphatidylinositol 3-kinase AKT protein Apoptosis Biocompatibility Bladder Bladder cancer Cancer Cancer therapies Cell cycle Chemotherapy Epidermal growth factor epidermal growth factor receptor (EGFR) Epidermal growth factor receptors Genes Growth factors Hesperidin high drug loading In vivo methods and tests Kinases Malignancy Nanoparticles Natural products NMR Nuclear magnetic resonance Proteins Receptors Self-assembly Software Solvents Succinic acid Survival Toxicity Triptolide Tyrosine |
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| Title | Small‐molecule nanoprodrug with high drug loading and EGFR, PI3K/AKT dual‐inhibiting properties for bladder cancer treatment |
| URI | https://www.ncbi.nlm.nih.gov/pubmed/37933289 https://www.proquest.com/docview/3092807416 https://www.proquest.com/docview/2886939434 https://doaj.org/article/42e6e8266d074b2e9cdc5f85d71ee913 |
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