首页|Restoring cellular calcium homeostasis to rescue ER stress by 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid acetoxymethyl ester-loaded lipid-mPLGA hybrid-nanoparticles for acute kidney injury therapy

Restoring cellular calcium homeostasis to rescue ER stress by 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid acetoxymethyl ester-loaded lipid-mPLGA hybrid-nanoparticles for acute kidney injury therapy

扫码查看
原文链接
  • NETL
  • NSTL
  • 万方数据
Early pathogenesis of ischemia-reperfusion(I/R)-induced acute kidney injury(AKI)is dominated by in-tracellular calcium overload,which induces oxidative stress,intracellular energy metabolism disorder,in-flammatory activation,and a series of pathologic cascaded reactions that are closely intertwined with self-amplifying and interactive feedback loops,ultimately resulting in cell damage and kidney failure.Cur-rently,most nanomedicines originate from the perspective of antioxidant stress,which can only quench existing reactive oxide species(ROS)but cannot prevent the continuous production of ROS,resulting in insufficient efficacy.As a safe and promising drug,BAPTA-AM is hydrolyzed into BAPTA by intracel-lular esterase upon entering cells,which can rapidly chelate with overloaded Ca2+,restoring intracel-lular calcium homeostasis,thus inhibiting ROS regeneration at the source.Here,we designed a KTP-targeting peptide-modified yolk-shell structure of liposome-poly(ethylene glycol)methyl ether-block-poly(L-lactide-co-glycolic)(mPLGA)hybrid nanoparticles(＜100nm),with the characteristics of high encap-sulation rate,high colloid stability,facile modification,and prolonged blood circulation time.Once the BA/mPLGA@Lipo-KTP was targeted to the site of kidney injury,the cholesteryl hemisuccinate(CHEMS)in the phospholipid bilayer,as an acidic cholesterol ester,was protonated in the simulated inflamma-tory slightly acidic environment(pH 6.5),causing the liposomes to rupture and release the BA/mPLGA nanoparticles,which were then depolymerized by intracellular esterase.The BAPTA-AM was diffused and hydrolyzed to produce BAPTA,which can rapidly cut off the malignant loop of calcium overload/ROS gen-eration at its source,blocking the endoplasmic reticulum(ER)apoptosis pathway(ATF4-CHOP-Bax/Bcl-2,Casp-12-Casp-3)and the inflammatory pathway(TNF-α-NF-κB-IL-6 axes),thus alleviating patholog-ical changes in kidney tissue,thereby inhibiting the expression of renal tubular marker kidney injury molecule 1(Kim-1)(reduced by 82.9％)and also exhibiting prominent anti-apoptotic capability(TUNEL-positive ratio decreased from 40.2％to 8.3％),significantly restoring renal function.Overall,this research holds huge potential in the treatment of I/R injury-related diseases.

BAPTA-AMCalcium overloadAcid-responsiveAKIER stress

Jingwen Zhang、Jiahui Yan、Yanan Wang、Hong Liu、Xueping Sun、Yuchao Gu、Liangmin Yu、Changcheng Li、Jun Wu、Zhiyu He

展开 >

Frontiers Science Center for Deep Ocean Multispheres and Earth System,and Key Laboratory of Marine Chemistry Theory and Technology,Ministry of Education,Ocean University of China,Qingdao 266100,China

College of Chemistry and Chemical Engineering,Ocean University of China,Qingdao 266100,China

School of Medicine and Pharmacy,Ocean University of China,Qingdao 266003,China

Sanya Oceanographic Institution,Ocean University of China,Qingdao 572024,China

Bioscience and Biomedical Engineering Thrust,The Hong Kong University of Science and Technology(Guangzhou),Nansha,Guangzhou 511400,China

Division of Life Science,The Hong Kong University of Science and Technology,Hong Kong 999077,China

展开 >

Taishan Scholar Foundation of Shandong ProvinceHainan Provincial Joint Project of Sanya Yazhou Bay Science and Technology City国家自然科学基金中央高校基本科研业务费专项

tsqn2022110652021JJLH003782003673202113049

2024

10.1016/j.cclet.2023.108434

中国化学快报(英文版)
中国化学会

中国化学快报(英文版)

CSTPCD
影响因子：0.771
ISSN：1001-8417
年,卷(期)：2024.35(3)
  • 50