Peroxynitrite(ONOO^(-))is a highly reactive nitrogen species that plays pivotal roles in cell signal transduction and physiological or pathological progresses.However,commonly used ONOO^(-)optical imaging probes are s...Peroxynitrite(ONOO^(-))is a highly reactive nitrogen species that plays pivotal roles in cell signal transduction and physiological or pathological progresses.However,commonly used ONOO^(-)optical imaging probes are still hampered by high background/autofluorescence(fluorescence probe),short emission wavelength,or poor selectivity in the case of chemiluminescence.Herein,we report a facile method to prepare an activatable chemiluminescence probe(PPA-PEG)with good biocompatibility and functionality for in vivo autofluorescence-free imaging of ONOO^(-).The PPA-PEG consists of pyropheophorbide-a(PPA),a typical deep red photosensitizer that acts as both the recognition and signaling element,and 4-arm poly(ethylene glycol)(4-arm PEG),which improves the biosafety and water solubility of probe.These components can self-assemble into nanoparticles(namely PPA-PEG nanoprobe)in aqueous solution.The PPA-PEG nanoprobe showed an ultra-low chemiluminescence signal before interacting with ONOO^(-),but exhibited good selectivity,high sensitivity and a fast response toward ONOO^(-).The PPAPEG was successfully applied to image cellular ONOO^(-)changes,as well as the endogenous ONOO^(-)changes in inflammation models and subcutaneous or orthotopic hepatocellular carcinoma(HCC)tumors models in living mice.In vitro and in vivo studies verified the good detection and imaging capabilities of PPA-PEG for peroxynitrite,demonstrating suitable tissue penetration and a high signal-to-background ratio(SBR).Thus,our nanoprobe can serve as a valuable activatable chemiluminescence imaging tool for studying important peroxynitrite-related chemical and biological applications.展开更多
Photodynamic therapy(PDT)employs lasers to activate photosensitizers,generating reactive oxygen species(ROS)for tumor cell destruction.However,the extremely short half-life of ROS and limited diffusion range restrict ...Photodynamic therapy(PDT)employs lasers to activate photosensitizers,generating reactive oxygen species(ROS)for tumor cell destruction.However,the extremely short half-life of ROS and limited diffusion range restrict PDT’s therapeutic efficiency.Recent studies have shown that lysosome-targeted PDT can directly disrupt the“explosive depot”of tumor cells by triggering the release of abundant hydrolases from lysosomes.Nevertheless,existing lysosometargeted strategies rely predominantly on a single protonation mechanism,resulting in low targeted efficiency.To enhance lysosome-targeted bursting,this study adopted a dual-mode recognition strategy,combining“hydrophobic interactionaided fusion”with“charge-directed anchoring”.Specifically,pyropheophorbide-a(PPa)was employed as a model photosensitizer and covalently conjugated with alkyl tertiary amines of varying chain lengths(C1,C4,C8,and C12),yielding lysosome-targeted bursting photosensitizers(PPa1,PPa4,PPa8,and PPa12).Self-assembled nanoparticles(LPPa NPs)were then prepared to facilitate tumor delivery.The objective of this study was to determine the optimal chain length by evaluating the balance among ROS production efficiency,lysosomal targeted capability,and assembly stability of LPPa NPs.Notably,PPa4 NPs demonstrated superior cellular uptake,enhanced ROS generation,and effective lysosometargeted bursting,thereby markedly improving antitumor efficacy.In summary,the dual-mode recognition strategy offered an advanced strategy for enhancing the efficiency of PDT.展开更多
基金supported by the Major Research Projects for Young and Middle-aged Talent of Fujian Provincial Health Commission(2021ZQNZD013)the Medical Innovation Project of Fujian Province(2021CXA043)+4 种基金the National Natural Science Foundation of China(62275050,62175031,and 22274023)the Natural Science Foundation of Fujian Province(2023J05093 and 2024J011224)the Scientific Foundation of Fuzhou Municipal Health Commission(2022-S-wt3),the Scientific Foundation of Fuzhou Municipal Health Commission(2022-S-rc1),the Scientific Foundation of Fuzhou Municipal Health Commission(2021-S-wp1)the Fujian Provincial Clinical Research Center for Hepatobiliary and Pancreatic Tumors(2020Y2013)the Fuzhou“14th Five-Year”Clinical Key Specialty(20220203)。
文摘Peroxynitrite(ONOO^(-))is a highly reactive nitrogen species that plays pivotal roles in cell signal transduction and physiological or pathological progresses.However,commonly used ONOO^(-)optical imaging probes are still hampered by high background/autofluorescence(fluorescence probe),short emission wavelength,or poor selectivity in the case of chemiluminescence.Herein,we report a facile method to prepare an activatable chemiluminescence probe(PPA-PEG)with good biocompatibility and functionality for in vivo autofluorescence-free imaging of ONOO^(-).The PPA-PEG consists of pyropheophorbide-a(PPA),a typical deep red photosensitizer that acts as both the recognition and signaling element,and 4-arm poly(ethylene glycol)(4-arm PEG),which improves the biosafety and water solubility of probe.These components can self-assemble into nanoparticles(namely PPA-PEG nanoprobe)in aqueous solution.The PPA-PEG nanoprobe showed an ultra-low chemiluminescence signal before interacting with ONOO^(-),but exhibited good selectivity,high sensitivity and a fast response toward ONOO^(-).The PPAPEG was successfully applied to image cellular ONOO^(-)changes,as well as the endogenous ONOO^(-)changes in inflammation models and subcutaneous or orthotopic hepatocellular carcinoma(HCC)tumors models in living mice.In vitro and in vivo studies verified the good detection and imaging capabilities of PPA-PEG for peroxynitrite,demonstrating suitable tissue penetration and a high signal-to-background ratio(SBR).Thus,our nanoprobe can serve as a valuable activatable chemiluminescence imaging tool for studying important peroxynitrite-related chemical and biological applications.
基金National Natural Science Foundation of China(No.82204318)Liaoning Revitalization Talents Program(Nos.XLYC22202019,and XLYC2203083)+3 种基金Natural Science Foundation of Henan,Guided Youth Science Fund Project(No.242300420424)Henan Eye Hospital Basic Science Research Program(No.25JCQN004)Key research and development program of Liaoning Province(No.2024JH2/102500061)Youth innovation team of Liaoning Province Department of Education(No.LJ222410163049).
文摘Photodynamic therapy(PDT)employs lasers to activate photosensitizers,generating reactive oxygen species(ROS)for tumor cell destruction.However,the extremely short half-life of ROS and limited diffusion range restrict PDT’s therapeutic efficiency.Recent studies have shown that lysosome-targeted PDT can directly disrupt the“explosive depot”of tumor cells by triggering the release of abundant hydrolases from lysosomes.Nevertheless,existing lysosometargeted strategies rely predominantly on a single protonation mechanism,resulting in low targeted efficiency.To enhance lysosome-targeted bursting,this study adopted a dual-mode recognition strategy,combining“hydrophobic interactionaided fusion”with“charge-directed anchoring”.Specifically,pyropheophorbide-a(PPa)was employed as a model photosensitizer and covalently conjugated with alkyl tertiary amines of varying chain lengths(C1,C4,C8,and C12),yielding lysosome-targeted bursting photosensitizers(PPa1,PPa4,PPa8,and PPa12).Self-assembled nanoparticles(LPPa NPs)were then prepared to facilitate tumor delivery.The objective of this study was to determine the optimal chain length by evaluating the balance among ROS production efficiency,lysosomal targeted capability,and assembly stability of LPPa NPs.Notably,PPa4 NPs demonstrated superior cellular uptake,enhanced ROS generation,and effective lysosometargeted bursting,thereby markedly improving antitumor efficacy.In summary,the dual-mode recognition strategy offered an advanced strategy for enhancing the efficiency of PDT.
