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  

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

机构地区：[1]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 [2]College of Chemistry and Chemical Engineering,Ocean University of China,Qingdao 266100,China [3]School of Medicine and Pharmacy,Ocean University of China,Qingdao 266003,China [4]Sanya Oceanographic Institution,Ocean University of China,Qingdao 572024,China [5]Bioscience and Biomedical Engineering Thrust,The Hong Kong University of Science and Technology(Guangzhou),Nansha,Guangzhou 511400,China [6]Division of Life Science,The Hong Kong University of Science and Technology,Hong Kong 999077,China

出　　处：《Chinese Chemical Letters》2024年第3期337-345,共9页中国化学快报（英文版）

基　　金：supported by the Taishan Scholar Foundation of Shandong Province(No.tsqn202211065);Hainan Provincial Joint Project of Sanya Yazhou Bay Science and Technology City(No.2021JJLH0037);the Natural Science Foundation of China(No.82003673);the Fundamental Research Funds for the Central Universities(No.202113049)。

摘　　要：Early pathogenesis of ischemia-reperfusion(I/R)-induced acute kidney injury(AKI)is dominated by intracellular calcium overload,which induces oxidative stress,intracellular energy metabolism disorder,inflammatory 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.Currently,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 intracellular esterase upon entering cells,which can rapidly chelate with overloaded Ca^(2+),restoring intracellular 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(<100 nm),with the characteristics of high encapsulation 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 inflammatory 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 generation 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 pathological changes in kidney tissue,thereby inhibiting the expression of renal tubular marker kidney injury molecule 1(Kim-1)(reduced by 82.9%)and

关 键 词：BAPTA-AM Calcium overload Acid-responsive AKI ER stress 

分 类 号：R692[医药卫生—泌尿科学] TQ460.1[医药卫生—外科学]