The Research On Acidic Microenvironment Stimuliresponsive Of Luminescent Gold Nanoparticles And Their Biological Imaging Applications

Due to the ultrasmall size,special optical properties,the feasibility of surface modification,kind biocompatibility and high renal clearance,luminous gold nanoparticles(AuNPs)have been favored by many researchers in the field of biosensor cell imaging and disease detection.In this paper,a series of ultrasmall AuNPs were prepared for the current challenges of disease imaging in organs.And combined with the acidic microenvironment of the related diseases,we discussed the surface plasmon resonance(SPR)absorption from these luminescence AuNPs controlled by p H.We also monitored the interaction between acidic tumor cells and the p H-sensitive AuNPs and explored the effects of the surface chemical properties in tumor targeting specificity,further investigated the fluorescence and ultrasonic multi-mode imaging for metabolic acidosis-induced early kidney injury.We provided a deeper understanding of the multi-mode imaging of luminescent AuNPs and expanded its application in biological imaging by controlling the surface chemistry.The detailed results are summarized as follow:Luminescent AuNPs with ultrasmall sizes(?2 nm)and few free electrons have attracted fundamental science and application research interests due to their robust emission properties,but discoveries on their fantastic plasmonic properties are limited.Herein,controllable surface plasmon resonance(SPR)absorption was reported from ultrasmall luminescent AuNPs coated with a small thiolate surface ligand,mercaptoimidazole(MZ),through p H regulation.The 690nm emitting MZ-AuNPs showed SPR absorption and emission with a reversibly p H-dependent response,i.e.,a strong emission with no SPR band at high p H values(e.g.,p H 5.0)and strong SPR absorption(570 nm)with weak emission at low p H values(e.g.,p H 2.0).The MZ surface coating,which has a low steric hindrance and high tendency to form intermolecular hydrogen bonds,is shown to play an important role in the creation of strong plasmon coupling and the emergence of plasmonic properties from ultrasmall MZ-AuNPs with 44%Au(I)species.To explore the biological application of luminescent AuNPs,here,we reported a surface regulation strategy that integrates the tumor-acidity-activated charge-reversal behavior and precise surface control in both hydrodynamic diameter(HD)and charge on the ultrasmall AuNPs to enhance the tumor cellular uptake.The introduction of a different amount of PEG-SH could precisely tune the HD and surface charge of AuNPs,and the conjugation of p H-responsive MIZ-H groups(p K_a?6.9)to control charge reversal of AuNPs under different p H.With the increase of PEG-SH,HDs of ultrasmall charge-reversal AuNPs increased from 2.4 to4.2 nm,?-potential values also increased from-31.2 to-11.4 m V at p H 7.4 and from 1.4 to 18.7m V at p H 6.5,but the charge-reversal abilities are similar.This surface regulation strategy enhanced significantly the membrane-binding and uptake of ultrasmall charge-reversal AuNPs in acid microenvironments,reaching 21.1 and 6.7 times by contrast that in neutral condition,respectively.The precise surface control in both HD and charge also enhanced the sensitivities of the ultrasmall AuNPs toward the tumor acidic microenvironments and increased the resistance to proteins,although the AuNPs showed similar charge-reversal abilities,which would facilitate the recognition of acidic tumor rather than normal tissues.The nanoprobes for identification of cancer metastases in the mononuclear phagocyte system(MPS)organs are of significant importance on both the pre-and post-cancer therapy,but are very limited due to the long-standing challenge of low tumor-targeting specificity with inadequate tumor-targeting efficiency and high nonspecific accumulation in the MPS organs.The imaging for cancer metastases in the mononuclear phagocyte system(MPS)organs was further investigated by using these ultrasmall charge-reversal AuNPs.We enhanced the significantly high tumor-targeting specificity for identification of cancer metastases by using aforementioned surface regulation strategy.It was found that the total clearance efficiency of AuNPs highly depends on the core sizes rather than HDs,and the precise regulation of ultrasmall charge-reversal AuNPs to a rational HD and surface charge could promote the response to tumor acidic microenvironment,prolonged blood circulation time,rapid renal clearance with low accumulation in MPS organs,and enhanced tumor-targeting specificity.The optimized charge-reversal AuNPs could rapidly and selectively recognize the small metastatic tumors(?1 mm)in liver and lung with signal-to-noise ratios as high as 4.6 and 4.5,respectively.These results help to understand furtherly the in vivo transport of metal nanoparticles,and provide guidance for design of nanosized nanomedicines toward future clinical practice in the cancer metastasis diagnose and treatment.In situ aggregation of ultrasmall luminescent AuNPs(PMIZ-AuNPs)in renal tubule cells enhanced the ultrasound contrast to diagnose the metabolic acidosis-induced kidney injury by fluorescence and ultrasonic imaging.Based on the aggregation of the ultrasmall luminescent AuNPs induced by injury renal acid microenvironment,the ultrasonic signals of AuNPs was discovered,which could be applied to the ultrasonic and fluorescence imaging in vivo.Such molecular imaging,coupled with detailed anatomical information,enabled us to accurately quantify the renal nephron of normal as well as diseased kidneys.The aggregation of renal clearable PMIZ-AuNPs in acidic environment enhanced the ultrasonic signal which provides a new low toxic contrast agent for fluorescence and ultrasound multi-mode imaging.