Abstract
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.
基金项目
Taishan Scholar Foundation of Shandong Province(tsqn202211065)
Hainan Provincial Joint Project of Sanya Yazhou Bay Science and Technology City(2021JJLH0037)
国家自然科学基金(82003673)
中央高校基本科研业务费专项(202113049)
NETL
NSTL
万方数据