Lipase-triggered drug release from BCL2 inhibitor ABT-199-loaded nanoparticles to elevate anti-leukemic activity through enhanced drug targeting on the mitochondrial membrane

doi:10.1016/j.actbio.2022.04.005

科研成果详情

题名	Lipase-triggered drug release from BCL2 inhibitor ABT-199-loaded nanoparticles to elevate anti-leukemic activity through enhanced drug targeting on the mitochondrial membrane
作者	Liang, Bin1; Jiang, Dawei 2; Pan, Luqi 2; Xiong, Fang3; Feng, Shuya3; Wu, Shenghao4; Ye, Haige5; Yu, Zhijie5; Shi, Changcan 2; Gao, Shenmeng3
发表日期	2022-06
发表期刊	Acta Biomaterialia 影响因子和分区
语种	英语
原始文献类型	Journal article (JA)
关键词	Biochemistry Cell culture Cell death Controlled drug delivery Diseases Drug interactions Mitochondria Motion Picture Experts Group standards Nanoparticles Polyethylene glycols Polyethylene oxides Targeted drug delivery ABT-199 Acute myeloid leukemia Amphiphilics BCL2 Block co polymers Clinical usage In-vitro MPEG-b-PTMC block copolymer Side effect Vitro and in vivo
其他关键词	IN-VIVO ; CERIA NANOPARTICLES ; LEUKEMIA ; VENETOCLAX ; DELIVERY ; CELLS ; GENE ; OVEREXPRESSION ; PROGENITOR ; RESISTANCE
摘要	Selective BCL2 inhibitor ABT-199 has been approved to treat hematological malignancies including acute myeloid leukemia (AML). However, acquired drug resistance and severe side effects occur after extended treatment limiting the clinical usage of ABT-199. Here, we successfully encapsulated pure ABT-199 in amphiphilic mPEG-b-PTMC169 block copolymer, forming mPEG-b-PTMC169@ABT-199 nanoparticles (abbreviated as PEG-ABT-199), which presented better aqueous dispersion and higher efficiency of loading and encapsulation than pure ABT-199. We then compared the anti-leukemic ability of pure ABT-199 and PEG-ABT-199 in vitro and in vivo. PEG-ABT-199 had a lower IC50 value compared with pure ABT-199 in MV4-11 and MOLM-13 cell lines. In addition, PEG-ABT-199 significantly induced apoptosis and decreased colony number than pure ABT-199. Most importantly, PEG-ABT-199 markedly reduced leukemic burden, inhibited the infiltration of leukemic blasts in the spleen, and extended the overall survival (OS) in MLL-AF9-transduced murine AML compared with free ABT-199. Meanwhile, the blank PEG169 NP was non-toxic to normal hematopoiesis in vitro and in vivo, suggesting that PEG169 NP is a safe carrier. Mechanistically, PEG-ABT-199 enhanced mitochondria-targeted delivery of ABT-199 to trigger the collapse of mitochondrial membrane potential (MMP), the release of cytochrome c (cyt-c), and mitochondria-based apoptosis. In conclusion, our results suggest that PEG-ABT-199 has more vital anti-leukemic ability than pure ABT-199. PEG-ABT-199 has potential application in clinical trials to alleviate side effects and improve anti-leukemia ability. Statement of significance: ATB-199, an orally selective inhibitor for BCL2 protein, presents marked activity in relapsed or refractory AML, T-ALL, and CLL patients. However, ABT-199 resistance severely limits the further clinical usage because of off-target effects, non-specific toxicities, and low delivery of drugs. To reduce the side-effects and improve the solubility and bioavailability, ABT-199 was encapsulated into the amphiphilic mPEG-b-PTMC block copolymer by co-assembly method to obtain mPEG-b-PTMC@ABT-199 nanoparticles (PEG-ABT-199). PEG-ABT-199 has several advantages compared with pure ABT-199. 1.PEG-ABT-199 presents better aqueous dispersion and higher efficiencies of loading and encapsulation than pure ABT-199. 2. PEG-ABT-199 substantially enhances the anti-leukemic ability in vitro and in vivo compared with pure ABT-199. 3. PEG-ABT-199 has little effects on normal cells. 4. PEG-ABT-199 can reduce treatment cost. © 2022
资助项目	National Natural Science Foundation of China [81971991]; Zhejiang Provincial Natural Science Foundation of China [LY20H080004, LY20H080002]; China Postdoctoral Science Foundation [2021M693135]
出版者	Acta Materialia Inc
出版地	OXFORD
ISSN	1742-7061
EISSN	1878-7568
卷号	145 页码:246-259
DOI	10.1016/j.actbio.2022.04.005
页数	14
WOS类目	Engineering, Biomedical ; Materials Science, Biomaterials
WOS研究方向	Engineering ; Materials Science
WOS记录号	WOS:000806509800003
收录类别	EI ; SCIE ; PUBMED ; SCOPUS
EI入藏号	20221712032388
EI主题词	Block copolymers
EI分类号	461.2 Biological Materials and Tissue Engineering ; 461.6 Medicine and Pharmacology ; 461.9 Biology ; 723.2 Data Processing and Image Processing ; 742.1 Photography ; 761 Nanotechnology ; 801.2 Biochemistry ; 802.2 Chemical Reactions ; 815.1 Polymeric Materials ; 815.1.1 Organic Polymers ; 933 Solid State Physics
URL	查看原文
PubMed ID	35405327
SCOPUSEID	2-s2.0-85128690381
通讯作者地址	[Shi, Changcan]Wenzhou Institute,University of Chinese Academy of Sciences,Laboratory of Internal Medicine,the First Affiliated Hospital of Wenzhou Medical University,1 Jinlian Road, Longwan District 1 Xuefubei Street, Ouhai District, Zhejiang Province Zhejiang Province,Wenzhou Wenzhou,325000 325000,China
Scopus学科分类	Biotechnology;Biomaterials;Biochemistry;Biomedical Engineering;Molecular Biology
TOP期刊	TOP期刊
引用统计	被引频次[WOS]：0 [WOS记录] [WOS相关记录]
文献类型	期刊论文
条目标识符	https://kms.wmu.edu.cn/handle/3ETUA0LF/153476
专题	附属第一医院附属第二医院
通讯作者	Shi, Changcan
作者单位	1.Department of Medical Oncology,the First Affiliated Hospital of Wenzhou Medical University,1 Xuefubei Street, Ouhai District, Zhejiang Province,Wenzhou,325000,China; 2.Wenzhou Institute,University of Chinese Academy of Sciences,1 Jinlian Road, Longwan District, Zhejiang Province,Wenzhou,325000,China; 3.Medical Research Center,the First Affiliated Hospital of Wenzhou Medical University,1 Xuefubei Street, Ouhai District, Zhejiang Province,Wenzhou,325000,China; 4.Department of Hematology,The Second Affiliated Hospital of Shanghai University (The Dingli Clinical Institute of Wenzhou Medical University,Wenzhou Central Hospital),No.252 East Baili Road, Lucheng District, Zhejiang Province,Wenzhou,325000,China; 5.Department of Hematology,the First Affiliated Hospital of Wenzhou Medical University,1 Xuefubei Street, Ouhai District, Zhejiang Province,Wenzhou,325000,China
第一作者单位	附属第一医院
通讯作者单位	附属第一医院
第一作者的第一单位	附属第一医院
推荐引用方式 GB/T 7714	Liang, Bin,Jiang, Dawei,Pan, Luqi,et al. Lipase-triggered drug release from BCL2 inhibitor ABT-199-loaded nanoparticles to elevate anti-leukemic activity through enhanced drug targeting on the mitochondrial membrane[J]. Acta Biomaterialia,2022,145:246-259.
APA	Liang, Bin., Jiang, Dawei., Pan, Luqi., Xiong, Fang., Feng, Shuya., ... & Gao, Shenmeng. (2022). Lipase-triggered drug release from BCL2 inhibitor ABT-199-loaded nanoparticles to elevate anti-leukemic activity through enhanced drug targeting on the mitochondrial membrane. Acta Biomaterialia, 145, 246-259.
MLA	Liang, Bin,et al."Lipase-triggered drug release from BCL2 inhibitor ABT-199-loaded nanoparticles to elevate anti-leukemic activity through enhanced drug targeting on the mitochondrial membrane".Acta Biomaterialia 145(2022):246-259.