Bioorthogonal Cyclization-Mediated In Situ Self-Assembly of Small Molecule Probes for Imaging Caspase Activity in vivo

Directed self-assembly of small molecules in living systems could enable a myriad of applications in biology and medicine, and it has been widely used to synthesize supramolecules and nano/microstructures in solution and in living cells. However, controlling self-assembly of synthetic small molecules in living animals is challenging because of the complex and dynamic in vivo physiological environment. Here we employed an optimized first-order bioorthogonal cyclization reaction to control self-assembly of a fluorescent small molecule, and demonstrated its in vivo applicability by imaging of casapae-3/7 activity in human tumor xenograft mouse models of chemotherapy. The in situ assembled fluorescent nanoparticles have been successfully imaged in both apoptotic cells and tumor tissues using three-dimensional structured illumination microscopy. This strategy combines the advantages offered by small molecules with those of nanomaterials and should find widespread use for non-invasive imaging of enzyme activity in vivo.

• Publication year

  2014

• Venue

  Nature Chemistry

• Publication date

  2014-04-26

• Fields of study

  Biology, Medicine, Chemistry

• Identifiers
  DOI 10.1038/nchem.1920PMID 24848238PMCID 4031611
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Strategy for dual-analyte luciferin imaging: in vivo bioluminescence detection of hydrogen peroxide and caspase activity in a murine model of acute inflammation.

  2013cited by this paper
• Controlled intracellular self-assembly of gadolinium nanoparticles as smart molecular MR contrast agents

  2013cited by this paper
• Reactive polymer enables efficient in vivo bioorthogonal chemistry

  2012cited by this paper
• Reaction-based small-molecule fluorescent probes for chemoselective bioimaging.

  2012cited by this paper
• Caspase-activated cell-penetrating peptides reveal temporal coupling between endosomal release and apoptosis in an RGC-5 cell model.

  2012cited by this paper
• Genetically encoded norbornene directs site-specific cellular protein labelling via a rapid bioorthogonal reaction.

  2012cited by this paper
• Fluorescent Nanoprobes Dedicated to in Vivo Imaging: From Preclinical Validations to Clinical Translation

  2012cited by this paper
• An inhibitor of glutathione S-transferase omega 1 that selectively targets apoptotic cells.

  2012cited by this paper
• A Pictet-Spengler ligation for protein chemical modification

  2012cited by this paper
• Phenylalanine assembly into toxic fibrils suggests amyloid etiology in phenylketonuria.

  2012cited by this paper
• Imaging enzyme-triggered self-assembly of small molecules inside live cells

  2012cited by this paper
• From Mechanism to Mouse: A Tale of Two Bioorthogonal Reactions

  2011cited by this paper
• Functional imaging of proteases: recent advances in the design and application of substrate-based and activity-based probes.

  2011cited by this paper
• The in vivo performance of an enzyme-assisted self-assembled peptide/protein hydrogel.

  2011cited by this paper
• Multi-hierarchical self-assembly of a collagen mimetic peptide from triple helix to nanofibre and hydrogel.

  2011cited by this paper
• Advances in the chemistry of small molecule fluorescent probes.

  2011cited by this paper
• On-demand drug delivery from self-assembled nanofibrous gels: a new approach for treatment of proteolytic disease.

  2011cited by this paper
• Noninvasive imaging of cell death using an Hsp90 ligand.

  2011cited by this paper
• Palladium-mediated intracellular chemistry.

  2011cited by this paper
• Controlling intracellular macrocyclization for the imaging of protease activity.

  2011cited by this paper
• In vivo imaging of tumor apoptosis using histone H1-targeting peptide.

  2010cited by this paper
• Bioinspired chemistry: Diversity for self-assembly.

  2010cited by this paper
• A biocompatible condensation reaction for controlled assembly of nanostructures in live cells

  2010cited by this paper
• Blood levels of homocysteine, cysteine, glutathione, folic acid, and vitamin B12 in the acute phase of atherothrombotic stroke

  2009cited by this paper
• Positron emission tomography imaging of drug-induced tumor apoptosis with a caspase-3/7 specific [18F]-labeled isatin sulfonamide

  2009cited by this paper
• Noninvasive optical imaging of apoptosis by caspase-targeted activity-based probes

  2009cited by this paper
• Fast and sensitive pretargeted labeling of cancer cells through a tetrazine/trans-cyclooctene cycloaddition.

  2009cited by this paper
• A biocompatible condensation reaction for the labeling of terminal cysteine residues on proteins.

  2009cited by this paper
• An improved cell-penetrating, caspase-activatable, near-infrared fluorescent peptide for apoptosis imaging.

  2009cited by this paper
• In Vivo Imaging of Membrane-Associated Glycans in Developing Zebrafish

  2008cited by this paper
• New approaches for imaging tumour responses to treatment

  2008cited by this paper
• Video-Rate Far-Field Optical Nanoscopy Dissects Synaptic Vesicle Movement

  2008cited by this paper
• Subdiffraction Multicolor Imaging of the Nuclear Periphery with 3D Structured Illumination Microscopy

  2008cited by this paper
• In Vivo Detection of Apoptosis

  2008cited by this paper
• Visualizing metabolically labeled glycoconjugates of living cells by copper-free and fast huisgen cycloadditions.

  2008cited by this paper
• Self-Assembly of Large and Small Molecules into Hierarchically Ordered Sacs and Membranes

  2008cited by this paper
• Enzymatic hydrogelation of small molecules.

  2008cited by this paper
• Tetrazine ligation: fast bioconjugation based on inverse-electron-demand Diels-Alder reactivity.

  2008cited by this paper
• Virtual Computational Chemistry Laboratory – Design and Description

  2005cited by this paper
• Mechanistic investigation of the staudinger ligation.

  2005cited by this paper
• A strain-promoted [3 + 2] azide-alkyne cycloaddition for covalent modification of biomolecules in living systems.

  2004cited by this paper
• Chemical remodelling of cell surfaces in living animals

  2004cited by this paper
• Doxorubicin Induces Apoptosis in Normal and Tumor Cells via Distinctly Different Mechanisms

  2004cited by this paper
• Interactions of fluorochrome‐labeled caspase inhibitors with apoptotic cells: A caution in data interpretation

  2003cited by this paper
• Staurosporine and conventional anticancer drugs induce overlapping, yet distinct pathways of apoptosis and caspase activation

  2001cited by this paper
• Cell surface engineering by a modified Staudinger reaction.

  2000cited by this paper
• A Combinatorial Approach Defines Specificities of Members of the Caspase Family and Granzyme B

  1997cited by this paper
• Molecular self-assembly and nanochemistry: a chemical strategy for the synthesis of nanostructures.

  1991cited by this paper
• THE CONCENTRATIONS OF CYSTEINE AND CYSTINE IN HUMAN BLOOD PLASMA.

  1960cited by this paper

• Bioorthogonal Molecular Turn-On Optical Imaging and Therapy.

  2026cites this paper
• Advances in cancer biomarkers: current detection strategies and challenges

  2026cites this paper
• Hydrogen-Bond Network-Directed Controllable Assembly of Stable Cyanine J-Aggregates for Long-Term and High-Contrast In Vivo Imaging.

  2026cites this paper
• Urinary bioorthogonal reporters for the monitoring of the efficacy of chemotherapy for lung cancer and of associated kidney injury

  2025cites this paper
• A dissipative hydrogel formed by peptide-carbon dioxide interaction

  2025cites this paper
• Achieving cell-type selectivity in metabolic oligosaccharide engineering

  2025cites this paper
• Dual-Locked Enzyme-Activatable Fluorescence Probes for Precise Bioimaging.

  2025cites this paper
• Aspartate Isomerization Regulates in Situ Assembly of Peptides into Supramolecular Probes for Detection of Protein Carboxyl Methyltransferase in Bladder Cancer.

  2025cites this paper
• Light-Controlled Intracellular Synthesis of Poly(luciferin) Polymers Induces Cell Paraptosis.

  2025cites this paper
• Supramolecular dyes: advancing precision medicine through molecular engineering.

  2025cites this paper
• Programming Nanostructure Formation Through Furin‐Triggered Isopeptide Conversion and Peptide Self‐Assembly

  2025cites this paper
• A TPP-OH-based near-infrared fluorescent nanoprobe for cellular and in vivo H2S detection and imaging.

  2025cites this paper
• Enhanced PET/MRI Hybrid Imaging of Prostate Cancer with In Situ Self-Assembled 68 Ga/Gd Nanoplatform

  2025cites this paper
• Self‐Assembled Fluorescent Peptide Nanoprobes for Disease Diagnosis

  2025cites this paper
• A Smart Self-Immobilization Magnetic Resonance Contrast Agent for Delayed Tumor Imaging In Vivo.

  2025cites this paper
• Translational contrast agents for use in fluorescence image-guided tumor surgery.

  2025cites this paper
• Self-Assembled Triple-Targeted Radiosensitizer Enhances Hypoxic Tumor Targeting and Radio-Immunotherapy Efficacy.

  2025cites this paper
• A DNA-MOF hybrid nanosystem for prediction of photodynamic therapy efficacy via amplified imaging of apoptotic mRNA

  2025cites this paper
• Super-Sensitive Chemiluminescent Probe for the Detection of Caspase‑3 Activity

  2025cites this paper
• Programming a multiplex lanthanide nanoparticle for customized cancer treatment with real-time efficiency feedback.

  2025cites this paper
• Tuning the efficiency of molecular probes via quinone methide-based in situ labeling

  2025cites this paper
• Cycling Molecular Assemblies (CyMA) for Ultrasensitive Golgi Imaging

  2025cites this paper
• Amphiphilic quinoline-malononitrile AIE probes: From molecule design to bio-applications

  2025cites this paper
• Recent advances in NIR small molecule activable probes for imaging and therapy

  2025cites this paper
• Intracellular co-self-assembly of 68Ga/Gd nanoparticles for enhanced PET/MRI hybrid imaging of orthotopic tumors

  2025cites this paper
• Electrochemical Investigation of Enzyme Kinetics with an Unmediated, Unmodified Platinum Microelectrode: The Case of Glucose Oxidase.

  2025cites this paper
• Intermediate Layer-Engineered Lanthanide Nanoparticles Enable Deep Bioorthogonal Liver Tumor and Vascular Imaging via Switchable NIR-II Emissions.

  2025cites this paper
• Caspase-3-Responsive Dual-Enhanced 1H/19F MRI Bimodal Probe for In Vivo Tumor Apoptosis Imaging.

  2025cites this paper
• Optical Nanoscopy for Elucidating Nano–Bio Interactions: A One Health Perspective

  2025cites this paper
• Nitrile-aminothiol bioorthogonal near-infrared fluorogenic probes for ultrasensitive in vivo imaging

  2025cites this paper
• Smart Molecular Imaging and Theranostic Probes by Enzymatic Molecular In Situ Self-Assembly

  2024cites this paper
• Self-Assembly in Living Cells: Bottom-Up Syntheses in Natural Factory.

  2024cites this paper
• Novel nano-capsule for targeted drug delivery and real-time therapeutic monitoring in osteosarcoma treatment

  2024cites this paper
• Integration of Hybridization Chain Reaction and Protein-Binding Amplification for Long-Term Imaging of Intracellular mRNA: Avoiding Signal Fluctuation.

  2024cites this paper
• Polypeptide Nanoparticles Conjugated with an NIR-II Organic Dye for TRPV1 Channel Blockade Enhance Mild phototheranostics.

  2024cites this paper
• Hierarchical supramolecules composed of starch-based nanocluster aggregates with light-responsive mechanical strain for remotely rapid and precise actuation.

  2024cites this paper
• Engineering two-in-one DNA nanohybrids to evaluate anti-cancer effects through activatable RNA imaging

  2024cites this paper
• Unnatural Peptide Assemblies Rapidly Deplete Cholesterol and Potently Inhibit Cancer Cells.

  2024cites this paper
• Catalytic Biomaterials‐Activated In Situ Chemical Reactions: Strategic Modulation and Enhanced Disease Treatment

  2024cites this paper
• Molecular Imaging of Renin Activity using Fluorogenic Nanoprobes for Precision Antihypertensive Therapy.

  2024cites this paper
• A Comprehensive Exploration of Caspase Detection Methods: From Classical Approaches to Cutting-Edge Innovations

  2024cites this paper
• Engineering Cyanine‐ and Hemicyanine‐Based Probes for Optical Imaging of Kidney Diseases

  2024cites this paper
• Controlled In Situ Self-Assembly of Biotinylated Trans-Cyclooctene Nanoparticles for Orthogonal Dual-Pretargeted Near-Infrared Fluorescence and Magnetic Resonance Imaging.

  2024cites this paper
• Activity-Independent Enzyme-Powered Amplification for Improving Signal Stability and Fidelity in Biosensing

  2024cites this paper
• Stimuli‐responsive linkers and their application in molecular imaging

  2024cites this paper
• Intracellular Chemical Reaction‐Induced Self‐Assembly for the Construction of Artificial Architecture and Its Functions

  2024cites this paper
• Mapping enzyme activity in living systems by real-time mid-infrared photothermal imaging of nitrile chameleons

  2024cites this paper
• Self-propelled assembly of nanoparticles with self-catalytic regulation for tumour-specific imaging and therapy

  2024cites this paper
• An artificial protein modulator reprogramming neuronal protein functions

  2024cites this paper
• A comprehensive review on peptide-bearing biomaterials: From ex situ to in situ self-assembly

  2024cites this paper
• Assembly‐Glued Ligands and Warheads for Hypoxia‐Activatable Supramolecular Covalent Inhibitors

  2024cites this paper
• Fluorescent Probes for Disease Diagnosis

  2024cites this paper
• Bioorthogonally activated probes for precise fluorescence imaging.

  2024cites this paper
• Size-transformable nanotherapeutics for cancer therapy

  2024cites this paper
• Self-assembly of peptides in living cells for disease theranostics.

  2024cites this paper
• Biocompatible strategies for peptide macrocyclisation

  2024cites this paper
• Colorimetric sensing for translational applications: from colorants to mechanisms.

  2024cites this paper
• Advancing Nitrile-Aminothiol Strategy for Dual and Sequential Bioconjugation.

  2024cites this paper
• Luminescence Nanoprobes for Drug Screening, Pharmaceutical Analysis, and Therapeutic Evaluations

  2023cites this paper
• Rigidity-Dependent Emission: Inspired Selection of an ATP-Specific Polyvalent Hydrogen Binding-Lighted Fluorophore for Intracellular Amplified Imaging.

  2023cites this paper
• Molecular-Based FRET Nanosensor with Dynamic Ratiometric NIR-IIb Fluorescence for Real-Time In Vivo Imaging and Sensing.

  2023cites this paper
• Orderly-Self-Assembly of Organic Fluorophores for Sensing and Imaging.

  2023cites this paper
• Empirical Optimization of Peptide Sequence and Nanoparticle Colloidal Stability: The Impact of Surface Ligands and Implications for Colorimetric Sensing.

  2023cites this paper
• A tumor-targetable NIR probe with photoaffinity crosslinking characteristics for enhanced imaging-guided cancer phototherapy

  2023cites this paper
• Metal-phenolic network for cancer therapy

  2023cites this paper
• Controlled sequential in situ self-assembly and disassembly of a fluorogenic cisplatin prodrug for cancer theranostics

  2023cites this paper
• Protease-Triggered, Spatially Controlled DNA Assembly in Apoptotic Cells for Early Evaluation of Therapeutic Efficacy.

  2023cites this paper
• Two birds one stone: β-fluoropyrrolyl-cysteine SNAr chemistry enabling functional porphyrin bioconjugation

  2023cites this paper
• Harnessing abiotic organic chemistry in living systems for biomedical applications.

  2023cites this paper
• An enzyme-instructed self-assembly system induces tumor acidosis via sequential-dual effect for cancer selective therapy.

  2023cites this paper
• Enzyme-Instructed CBT-Cys-like Click Cyclization Reactions for Bioimaging

  2023cites this paper
• Activatable organic probes for in situ imaging of biomolecules.

  2023cites this paper
• Harnessing the power of molecular imaging for drug discovery and development

  2023cites this paper
• Organelle-Mediated Dissipative Self-Assembly of Peptides in Living Cells.

  2023cites this paper
• A Dual-Mechanism Targeted Bioorthogonal Prodrug Therapy.

  2023cites this paper
• Therapeutic Supramolecular Polymers: Designs and Applications.

  2023cites this paper
• Cascade In Situ Self-Assembly and Bioorthogonal Reaction Enable the Enrichment of Photosensitizers and Carbonic Anhydrase Inhibitors for Pretargeted Cancer Theranostics.

  2023cites this paper
• Recent advances in fluorescence biosensor for caspase detecting and imaging in biomedical applications

  2023cites this paper
• A Smart Intracellular Self‐Assembling Bioorthogonal Raman Active Nanoprobe for Targeted Tumor Imaging

  2023cites this paper
• Application of stimuli responsive nanocomposites in drug delivery and theranostics to counter cancer proliferation and drug resistance

  2023cites this paper
• Activatable small molecular luminescence probes for autofluorescence-free bioimaging

  2023cites this paper
• Dual-Targeting PET Tracers Enable Enzyme-Mediated Self-Assembly for the PET Imaging of Legumain Activity.

  2023cites this paper
• Smart and bioinspired systems for overcoming biological barriers and enhancing disease theranostics

  2023cites this paper
• Nanoprobe-based molecular imaging for tumor stratification.

  2023cites this paper
• In situ self-assembly for cancer therapy and imaging

  2023cites this paper
• The Application of Bio-orthogonality for In Vivo Animal Imaging

  2023cites this paper
• Caspase-3-Triggered Intracellular Gadolinium Nanoparticle Formation for T1-Weighted Magnetic Resonance Imaging of Apoptosis In Vivo.

  2023cites this paper
• Enzyme-Instructed Aggregation/Dispersion of Fluorophores for Near-Infrared Fluorescence Imaging In Vivo

  2023cites this paper
• A Self-Assembled Organic Probe with Activatable Near-Infrared Fluoro-Photoacoustic Signals for In Vivo Evaluation of the Radiotherapy Effect.

  2023cites this paper
• Advances in Intracellular and On‐Surface Polymerization in Living Cells: Implications for Nanobiomedicines

  2023cites this paper
• Enzyme-Activatable Near-Infrared Photosensitizer with High Enrichment in Tumor Cells Based on a Multi-effect Design.

  2023cites this paper
• Designing bioresponsive nanomaterials for intracellular self-assembly

  2022cites this paper
• Spacer Matters: All-Peptide-Based Ligand for Promoting Interfacial Proteolysis and Plasmonic Coupling.

  2022cites this paper
• A Dual‐Locked Tandem Fluorescent Probe for Imaging of Pyroptosis in Cancer Chemo‐Immunotherapy

  2022cites this paper
• Visualization of supramolecular assembly by aggregation‐induced emission

  2022cites this paper
• Stimulus‐Responsive Amino Acids Behind In Situ Assembled Bioactive Peptide Materials

  2022cites this paper
• Granzyme B Turns Nanoparticle Fluorescence "On" for Imaging Cytotoxic T Lymphocyte Activity in Vivo.

  2022cites this paper
• In Vitro Self-Assembly of a Modified Diphenylalanine Peptide to Nanofibers Induced by the Eye Absent Enzyme and Alkaline Phosphatase and Its Activity against Breast Cancer Cell Proliferation.

  2022cites this paper
• Realization of firefly bioluminescence cycle in vitro and in cells.

  2022cites this paper
• Morphological Transformation and In Situ Polymerization of Caspase-3 Responsive Diacetylene-Containing Lipidated Peptide Amphiphile for Self-Amplified Cooperative Antitumor Therapy.

  2022cites this paper