中国科学院机构知识库网格
Chinese Academy of Sciences Institutional Repositories Grid
首页 机构 成果 学者
  
  1. CAS IR Grid
  2. 上海药物研究所
  3. 中国科学院上海药物研究所
  4. 新药研究国家重点实验室
Ultrasound-directed enzyme-prodrug therapy (UDEPT) self-immolative doxorubicin derivatives

文献类型：期刊论文

作者Roemhild, Karolin8,9,10; Besse, Helena C.7; Wang, Bi9,10; Pena, Quim9,10; Sun, Qingxue9,10; Omata, Daiki5,6; Ozbakir, Burcin6; Bos, Clemens7; Scheeren, Hans W.9,10; Storm, Gert3,4,6
刊名THERANOSTICS
出版日期2022
卷号12期号:10页码:4791-4801
ISSN号1838-7640
关键词Cancer Prodrugs Focused ultrasound HIFU beta-glucuronidase
DOI10.7150/thno.69168
通讯作者Deckers, Roel(R.Deckers-2@umcutrecht.nl) ; Shi, Yang(yshi@ukaachen.de) ; Lammers, Twan(tlammers@ukaachen.de)
英文摘要Background: Enzyme-activatable prodrugs are extensively employed in oncology and beyond. Because enzyme concentrations and their (sub)cellular compartmentalization are highly heterogeneous in different tumor types and patients, we propose ultrasound-directed enzyme-prodrug therapy (UDEPT) as a means to increase enzyme access and availability for prodrug activation locally. Methods: We synthesized beta-glucuronidase-sensitive self-immolative doxorubicin prodrugs with different spacer lengths between the active drug moiety and the capping group. We evaluated drug conversion, uptake and cytotoxicity in the presence and absence of the activating enzyme beta-glucuronidase. To trigger the cell release of beta-glucuronidase, we used high-intensity focused ultrasound to aid in the conversion of the prodrugs into their active counterparts. Results: More efficient enzymatic activation was observed for self-immolative prodrugs with more than one aromatic unit in the spacer. In the absence of beta-glucuronidase, the prodrugs showed significantly reduced cellular uptake and cytotoxicity compared to the parent drug. High-intensity focused ultrasound-induced mechanical destruction of cancer cells resulted in release of intact beta-glucuronidase, which activated the prodrugs, restored their cytotoxicity and induced immunogenic cell death. Conclusion: These findings shed new light on prodrug design and activation, and they contribute to novel UDEPT-based mechanochemical combination therapies for the treatment of cancer.
WOS关键词BETA-GLUCURONIDASE ; PHASE-I ; ANTHRACYCLINE PRODRUGS ; CANCER ; CHEMOTHERAPY ; CHEMISTRY ; EFFICACY ; TRIAL
资助项目European Research Council (ERC)[CoG 864121] ; European Research Council (ERC)[PoC 813086] ; European Research Council (ERC)[Adv 268906] ; China Scholarship Council (CSC) ; German Research Foundation[DFG: GRK 2375] ; German Research Foundation[331065168] ; German Research Foundation[SFB 1066] ; German Research Foundation[LA2937/4-1] ; German Research Foundation[SH 1223/1-1] ; Era-NET EuroNanoMed-3 program (NSC4DIPG)
WOS研究方向Research & Experimental Medicine
语种英语
出版者IVYSPRING INT PUBL
WOS记录号WOS:000809420200010
源URL[http://119.78.100.183/handle/2S10ELR8/301750]  
专题新药研究国家重点实验室
通讯作者Deckers, Roel; Shi, Yang; Lammers, Twan
作者单位1.Chinese Acad Sci, Shanghai Inst Mat Med, Ctr Pharmaceut, Shanghai 201203, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
3.Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Surg, Singapore 119074, Singapore
4.Univ Twente, Dept Targeted Therapeut, Enschede, Netherlands
5.Teikyo Univ, Fac Pharma Sci, Lab Drug & Gene Delivery Res, Tokyo, Japan
6.Univ Utrecht, Dept Pharmaceut, NL-3584 CG Utrecht, Netherlands
7.Univ Med Ctr Utrecht, Div Imaging & Oncol, NL-3584 CX Utrecht, Netherlands
8.Rhein Westfal TH Aachen, Inst Pathol, Uniklin RWTH Aachen, Fac Med, D-52074 Aachen, Germany
9.Rhein Westfal TH Aachen, Helmholtz Inst Biomed Engn, Fac Med, D-52074 Aachen, Germany
10.Rhein Westfal TH Aachen, Dept Nanomed & Theranost, Inst Expt Mol Imaging, Uniklin RWTH Aachen, D-52074 Aachen, Germany
推荐引用方式
GB/T 7714		 Roemhild, Karolin,Besse, Helena C.,Wang, Bi,et al. Ultrasound-directed enzyme-prodrug therapy (UDEPT) self-immolative doxorubicin derivatives[J]. THERANOSTICS,2022,12(10):4791-4801.
APA Roemhild, Karolin.,Besse, Helena C..,Wang, Bi.,Pena, Quim.,Sun, Qingxue.,...&Lammers, Twan.(2022).Ultrasound-directed enzyme-prodrug therapy (UDEPT) self-immolative doxorubicin derivatives.THERANOSTICS,12(10),4791-4801.
MLA Roemhild, Karolin,et al."Ultrasound-directed enzyme-prodrug therapy (UDEPT) self-immolative doxorubicin derivatives".THERANOSTICS 12.10(2022):4791-4801.

入库方式： OAI收割

来源：上海药物研究所

浏览0
下载0
收藏0
其他版本

除非特别说明，本系统中所有内容都受版权保护，并保留所有权利。