Antioxidant Nanoreporter For Early Diagnosis And Amelioration Of Drug Induced Acute Kidney Injury

Acute kidney injury(AKI),a disease defined as a rapid decline of renal function,has emerged as a global health concern due to the high rate of morbidity and mortality.Significantly,as typical anticancer drug cisplatin has shown strong nephrotoxicity and induced AKI.Currently,clinical diagnostic approach relies on the detection of serum creatinine and blood urea nitrogen,making it difficult to achieve accurate early diagnosis of AKI.Traditional imaging methods such as magnetic resonance and ultrasound manners have been employed for AKI diagnosis via non-invasive method,but there is still a lack of detection of AKI related biomarkers at the molecular level.Latest studies have revealed that,O2·-could serve as a kind of AKI-associated molecular biomarker,and show high promise for AKI early detection.In this paper,we explore the application of nanoprobe and nanoenzyme using superoxide free radicals as biomarkers in the early diagnosis and amelioration of acute kidney injury.The main contents are described as follows:Chapter 1:The application of optical probe in the early diagnosis of acute kidney injury is briefly described.The research status of nanomaterials in ameliorating acute kidney injury is summarized.On this basis,we discuss the research background,significance and research contents.Chapter 2:We report the synthesis of supramolecularly engineered chemiluminescence(CL)reporters,i.e.,L-serine-modified PLGA encapsulated peroxyoxalate(CPPO),chlorin e6(Ce6)and superoxide dismutase(SOD),which is short for PCCS,through "water-in-oil-in-water" approach for early diagnosing and ameliorating drug-induced acute kidney injury(AKI).In this system,under the catalysis of SOD,the biomarker(superoxide anion,i.e.,O2·-)of AKI will trigger the oxidation of CPPO and CL resonance energy transfer from 1,2-dioxetanedione to Ce6.Moreover,the L-serine-modified PLGA with kidney injury molecule-1 targeting ability can also stabilize the chemiexcitation reaction via controlling hydrogen bond/π一π stacking,generating long-lived CL emission(half-lives:～1000 s).Transcriptomics analysis demonstrates the PCCS can reduce inflammation response through glutathione metabolism and tumor necrosis factor signaling pathways.These advantages allow PCCS to non-invasively detect AKI at least 12 h earlier than current assays,and their antioxidant property also permits the early diagnosis and amelioration of AKI,simultaneously.Chapter 3:In order to deal with the damage of kidney tissue caused by the explosive generation of reactive oxygen species(ROS)in the process of drug induction,a double atom nanoenzyme(FeCo-NC)co-doped with Fe and Co is synthesized.First,ZIF-8 is prepared by self-assembly of zinc nitrate(ZnNO3)and 2-methylimidazole(2-MI)in methanol solution,and then Fe3+ and Co2+ ions are introduced by chemical doping method.After pyrolysis at high temperature,the precursor of ZIF-8 co-doped with Fe and Co is transformed into atomic dispersed nitrogen coordination single metal sites and embedded in the carbon framework.The experimental results show that the designed FeCo-NC exhibits higher superoxide dismutase activity and catalase activity than the monatomic nanoenzyme(increased by 3.2 times and 3.8 times respectively).The results from in vitro and in vivo show that the dual enzyme antioxidant FeCo-NC could effectively eliminate ROS ameliorate the damage of kidney tissue caused by anticancer drug.Chapter 4:We summarize the research content of this paper.The innovation and shortcomings of this work are also hightlighten,and then look forward to the future research direction.We first synthesize an antioxidant chemiluminescence reporter by the method of"water-in-oil-in-water",which can simultaneously image and ameliorate drug-induced acute kidney injury.Secondly,a diatomic nanoenzyme with atomic monodispersity is prepared.The experimental results show that the synthesized diatomic antioxidant nanoreporter exhibites higher catalytic activity than the monoatomic nanoenzyme,which can effectively eliminate ROS produced in cells and alleviate the damage to renal tissue caused by ROS produced during drug induction.The above two nanoreporting devices provide a new idea for early diagnosis and amelioration of drug-induced acute kidney injury.