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Confined copper depletion via a hydrogel platform for reversing dabrafenib/cetuximab resistance in BRAFV600E-mutant V600E-mutant colorectal cancer

文献类型：期刊论文

作者Wang, Jue2,4,5; Sun, Xiangshi4,5; Zhao, Zhiwen2,4,5; Wang, Guanru4,5; Wang, Dangge3; Li, Yaping1,2,4,5
刊名JOURNAL OF CONTROLLED RELEASE
出版日期2024-11-01
卷号375页码:11
关键词Colorectal cancer Copper depletion Drug resistance Hydrogel Nanoparticles
ISSN号0168-3659
DOI10.1016/j.jconrel.2024.09.034
通讯作者Wang, Dangge(dg_wang@sjtu.edu.cn) ; Li, Yaping(ypli@simm.ac.cn)
英文摘要BRAFV600E-mutant V600E-mutant colorectal cancer (CRC) is resistant to most first-line therapeutics, including the BRAF inhibitor dabrafenib and epidermal growth factor receptor (EGFR) inhibitor cetuximab. Although copper depletion shows promise in reversing dabrafenib/cetuximab resistance in BRAFV600E-mutant V600E-mutant CRC, its application is limited by the potential for excessive copper depletion in non-tumor objects. In this study, we have developed a hydrogel platform for confined copper depletion in BRAFV600E-mutant V600E-mutant CRC cells, which effectively reverses dabrafenib/ cetuximab resistance and enhancing therapeutic efficiency. The hydrogel platform enables precise intracellular copper depletion through localized administration, acidity-triggered drug release, and oxidized activation of a copper prochelator. The dosage of this prochelator is 37.5 mu g/kg in mouse models, which is significantly lower than the commonly used tetrathiomolybdate. Furthermore, both dabrafenib and the prochelator are preloaded into acid-responsive nanoparticles before being embedded in the hydrogel matrix to facilitate efficient endocytosis and acid-activatable drug release. Confined copper depletion inhibits MEK1 signaling and suppresses the MAPK signaling pathway when combined with BRAF and EGFR inhibitors. Moreover, the hydrogel platform inhibits tumor growth and prolongs survival in subcutaneous and postsurgical models of BRAFV600E-mutant V600E-mutant CRC. This study provides an innovative strategy for overcoming dabrafenib/cetuximab resistance in BRAFV600E- V600E- mutant CRC through precise intracellular copper depletion.
WOS关键词OXIDATIVE STRESS ; BRAF ; INHIBITION ; EFFICACY ; ACTIVATION ; CETUXIMAB ; THERAPY
资助项目National Key Research and Development Program of China[2022YFC3401404] ; National Natural Science Foundation of China[32170935] ; National Natural Science Foundation of China[31930066] ; Shanghai Rising-star Program[23QA1411200] ; Shandong Laboratory Program[SYS202205]
WOS研究方向Chemistry ; Pharmacology & Pharmacy
语种英语
WOS记录号WOS:001322736700001
出版者ELSEVIER
源URL[http://119.78.100.183/handle/2S10ELR8/313672]  
专题新药研究国家重点实验室
通讯作者Wang, Dangge; Li, Yaping
作者单位1.Bohai Rim Adv Res Inst Drug Discovery, Shandong Lab Yantai Drug Discovery, Yantai 264117, Shandong, Peoples R China
2.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
3.Shanghai Jiao Tong Univ, Shanghai Gen Hosp, Precis Res Ctr Refractory Dis, Sch Med, Shanghai 201620, Peoples R China
4.Chinese Acad Sci, Shanghai Inst Mat Med, Ctr Pharmaceut, Shanghai 201203, Peoples R China
5.Chinese Acad Sci, State Key Lab Drug Res, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Wang, Jue,Sun, Xiangshi,Zhao, Zhiwen,et al. Confined copper depletion via a hydrogel platform for reversing dabrafenib/cetuximab resistance in BRAFV600E-mutant V600E-mutant colorectal cancer[J]. JOURNAL OF CONTROLLED RELEASE,2024,375:11.
APA Wang, Jue,Sun, Xiangshi,Zhao, Zhiwen,Wang, Guanru,Wang, Dangge,&Li, Yaping.(2024).Confined copper depletion via a hydrogel platform for reversing dabrafenib/cetuximab resistance in BRAFV600E-mutant V600E-mutant colorectal cancer.JOURNAL OF CONTROLLED RELEASE,375,11.
MLA Wang, Jue,et al."Confined copper depletion via a hydrogel platform for reversing dabrafenib/cetuximab resistance in BRAFV600E-mutant V600E-mutant colorectal cancer".JOURNAL OF CONTROLLED RELEASE 375(2024):11.

入库方式： OAI收割

来源：上海药物研究所

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