An enzyme-responsive double-locked amonafide prodrug for the treatment of glioblastoma with minimal side effects.

Amonafide (ANF), a topoisomerase II inhibitor and DNA intercalator, has exhibited promise in phase II trials but faces significant limitations due to adverse side effects. Here, we have developed a novel enzyme-triggered fluorogenic prodrug, AcKLP, that incorporates dual-locked enzyme activation, ensuring that the prodrug remains inactive until it confronts the unique enzymatic environment of glioblastoma cells. This approach minimizes premature activation and reduces toxicity to normal cells, with an IC > 100 μM for human umbilical vein endothelial cells (HUVEC) and ∼2.

Intraoperative evaluation of tumor margins using a TROP2 near-infrared imaging probe to enable human breast-conserving surgery.

Intraoperative surgical margin assessment remains a challenge during breast-conserving surgery. Here, we report a combined strategy of immuno-positron emission tomography (PET) for preoperative detection of breast cancer and guided assessment of margins in breast-conserving surgery through second near-infrared (NIR-II) fluorescence imaging of trophoblastic cell surface antigen 2 (TROP2). We demonstrated that the intensity of PET signals in the tumors was nearly five times higher than in normal breast tissue with a zirconium-89 tracer conjugated to sacituzumab govitecan (SG) in a mouse spontaneous breast cancer model, enabling the identification of tumors.

An antagonist-based two-photon fluorogenic probe for imaging metabotropic glutamate receptor 5 in neuronal cells.

The expression of metabotropic glutamate receptor 5 (mGluR5) is subject to developmental regulation and undergoes significant changes in neuropsychiatric disorders and diseases. Visualizing mGluR5 by fluorescence imaging is a highly desired innovative technology for biomedical applications. Nevertheless, there are substantial problems with the chemical probes that are presently accessible.

Cascading Detection of Hydrogen Sulfide and -Acetyltransferase 2 in Hepatocellular Carcinoma Cells Using a Two-Photon Fluorescent Probe.

Hydrogen sulfide (HS), a critical gas signaling molecule, and -acetyltransferase 2 (NAT2), a key enzyme in drug metabolism, are both known active biomarkers for liver function. However, the interactions and effects of HS and NAT2 in living cells or lesion sites remain unknown due to the lack of imaging tools to achieve simultaneous detection of these two substances, making it challenging to implement real-time imaging and precise tracking. Herein, we report an activity-based two-photon fluorescent probe, , for the cascade detection of HS and NAT2 in living liver cells.

Activatable Dual-Optical Molecular Probe for Bioimaging Superoxide Anion in Epilepsy.

Superoxide anion (O) plays a pivotal role in the generation of other reactive oxygen species within the body and is closely linked to epilepsy. Despite this connection, achieving precise imaging of O during epilepsy pathology remains a formidable challenge. Herein, we develop an activatable molecular probe, , to track the fluctuation of the level of O in epilepsy through simultaneous fluorescence imaging and chemiluminescence sensing.

Novel 1,8-Naphthalimide Derivatives As Antitumor Agents and Potent Demethylase Inhibitors.

Functional 1,8-naphthalimide derivatives are rapidly developing in the field of anticancer research. Herein, we designed and synthesized a series of naphthalimide derivatives with different substituents. Interestingly, 1,8-naphthalimide derivatives and inhibited a human demethylase FTO (the fat mass and obesity-associated protein).

Novel Dual-Mode NIR-II/MRI Nanoprobe Targeting PD-L1 Accurately Evaluates the Efficacy of Immunotherapy for Triple-Negative Breast Cancer.

Background: Durable responses to immune-checkpoint blocking therapy (ICT) targeting programmed cell death protein-1/ligand-1 (PD-1/PD-L1) have improved outcomes for patients with triple negative breast cancer (TNBC). Unfortunately, only 19-23% of patients benefit from ICT. Hence, non-invasive strategies evaluating responses to therapy and selecting patients who will benefit from ICT are critical issues for TNBC immunotherapy.

Macrophage Reprogramming via Targeted ROS Scavenging and COX-2 Downregulation for Alleviating Inflammation.

Inflammation-related diseases affect large populations of people in the world and cause substantial healthcare burdens, which results in significant costs in time, material, and labor. Preventing or relieving uncontrolled inflammation is critical for the treatment of these diseases. Herein, we report a new strategy for alleviating inflammation by macrophage reprogramming via targeted reactive oxygen species (ROS) scavenging and cyclooxygenase-2 (COX-2) downregulation.

Water-Soluble Chemically Precise Fluorinated Molecular Clusters for Interference-Free Multiplex F MRI in Living Mice.

Fluorine-19 magnetic resonance imaging (F MRI) is gaining widespread interest from the fields of biomolecule detection, cell tracking, and diagnosis, benefiting from its negligible background, deep tissue penetration, and multispectral capacity. However, a wide range of F MRI probes are in great demand for the development of multispectral F MRI due to the limited number of high-performance F MRI probes. Herein, we report a type of water-soluble molecular F MRI nanoprobe by conjugating fluorine-containing moieties with a polyhedral oligomeric silsesquioxane (POSS) cluster for multispectral color-coded F MRI.

Novel Self-Assembled Multifunctional Nanoprobes for Second-Near-Infrared-Fluorescence-Image-Guided Breast Cancer Surgery and Enhanced Radiotherapy Efficacy.

Breast-conserving surgery (BCS) is the predominant treatment approach for initial breast cancer. However, due to a lack of effective methods evaluating BCS margins, local recurrence caused by positive margins remains an issue. Accordingly, radiation therapy (RT) is a common modality in patients with advanced breast cancer.

Bio-orthogonal Metabolic Fluorine Labeling Enables Deep-Tissue Visualization of Tumor Cells In Vivo by F Magnetic Resonance Imaging.

The high resolution, deep penetration, and negligible biological background of F magnetic resonance imaging (MRI) makes it a potential means for imaging various biological targets in vivo. However, the limited targeting strategies of current F MRI probes significantly restrict their applications for in vivo tracking of low-abundance targets and specific biological processes, which greatly stimulates the investigations on new targeting methods for F MRI. Herein, we report a strategy, termed as bio-orthogonal metabolic fluorine labeling, for selective cellular F labeling, which permits in vivo imaging of tumor cells with high specificity.

Multicolor F magnetic resonance imaging: A promising medical technique for visualization of multiple biological targets.

Driven by the needs of precision medicine, current imaging techniques are under continuous development to offer more accurate and comprehensive information beyond traditional macroscopic anatomical images. Multispectral color-coded (multicolor) F magnetic resonance imaging (MRI) is receiving increasing attention owing to its capability for visualizing quantitative and multiplexed molecular information during various biological processes. The chemical design and preparation of F probes lie at the core of multicolor F MRI since their performance dominates the accomplishment of this technique.

F Barcoding Enables Multiplex Detection of Biomarkers Associated with Organ Injury and Cancer.

Simultaneous detection of multiple biomarkers in complex environments is critical for the in-depth exploration of different biological processes, which is challenging for many current analytical methods due to various limitations. Herein, we report a strategy of F barcoding which takes the advantages of F's high magnetic resonance (MR) sensitivity, prompt signal response to environmental changes, negligible biological background, quantitative signal output, and multiplex capacity. A set of F-barcoded sensors responding to different biomarkers involved in organ injury and cancer are designed, synthesized, and characterized.

A dual-responsive doxorubicin-indoximod conjugate for programmed chemoimmunotherapy.

Herein we report a dual-responsive doxorubicin-indoximod conjugate (DOXIND) for programmed chemoimmunotherapy. This conjugate is able to release doxorubicin and indoximod upon exposure to appropriate stimuli for synergistic chemotherapy and immunotherapy, respectively. We demonstrate its promoting effects on immune response and inhibiting effects on tumor growth through a series of and experiments.

Photoinduced Superhydrophilicity of Gd-Doped TiO Ellipsoidal Nanoparticles Boosts Contrast Enhancement for Magnetic Resonance Imaging.

The unsatisfactory performance of current gadolinium chelate based contrast agents (CAs) for magnetic resonance imaging (MRI) stimulates the search for better alternatives. Herein, we report a new strategy to substantially improve the capacity of nanoparticle-based CAs by exploiting the photoinduced superhydrophilic assistance (PISA) effect. As a proof of concept, we synthesized citrate-coated Gd-doped TiO ellipsoidal nanoparticles (GdTi-SC NPs), whose increases significantly upon UV irradiation.

Tandem Chemoimmunotherapy by a Cascade-Responsive Molecular Prodrug.

The limited therapeutic effects of immunotherapy for most types of cancer stimulates the pursuit for efficient methods to improve its response rate. Herein we report the design and synthesis of a cascade-responsive molecular prodrug for tandem chemoimmunotherapy. This molecular prodrug first releases doxorubicin (DOX) in the mildly acidic tumor microenvironment (TME) to induce immunogenic cell death (ICD) of tumor cells.

Activatable Multiplexed F Magnetic Resonance Imaging Visualizes Reactive Oxygen and Nitrogen Species in Drug-Induced Acute Kidney Injury.

levels of reactive oxygen species (ROS) and reactive nitrogen species (RNS) are critical to many physiological and pathological processes. Because of the distinct differences in their biological generation and effects, simultaneously visualizing both of them could help deepen our insights into the mechanistic details of these processes. However, real-time and deep-tissue imaging and differentiation of ROS- and RNS-related molecular events in living subjects still remain a challenge.

Arsenite-loaded albumin nanoparticles for targeted synergistic chemo-photothermal therapy of HCC.

Arsenic trioxide (ATO, AsO), an active ingredient of traditional Chinese medicine, has been approved by the U.S. Food and Drug Administration as an effective therapeutic agent for acute promyelocytic leukemia (APL).

Redox-Activated Contrast-Enhanced -Weighted Imaging Visualizes Glutathione-Mediated Biotransformation Dynamics in the Liver.

GSH-mediated liver biotransformation is a crucial physiological process demanding efficient research tools. Here, we report a type of amorphous FeMnO nanoparticles (AFMO-ZDS NPs) as redox-activated probes for visualization of the dynamics of GSH-mediated biotransformation in liver with -weighted magnetic resonance imaging (MRI). This imaging technique reveals the periodic variations in GSH concentration during the degradation of AFMO-ZDS NPs due to the limited transportation capacity of GSH carriers in the course of GSH efflux from hepatocytes to perisinusoidal space, providing direct imaging evidence for this important carrier-mediated process during GSH-mediated biotransformation.

A camptothecin prodrug induces mitochondria-mediated apoptosis in cancer cells with cascade activations.

Mitochondria are crucial regulators of the intrinsic pathway of apoptosis. Herein, we report a photosensitizer-conjugated camptothecin (CPT)-based prodrug for combinative chemo-photodynamic treatment of solid tumors with cascade activations. Upon light irradiation, our prodrug can effectively target the mitochondria of cancer cells, generate singlet oxygen to increase the level of reactive oxygen species (ROS) and trigger ROS-responsive release of CPT, which synergistically induce mitochondrial damage and cause the apoptosis of cancer cells, therefore achieving high therapeutic efficacy for solid tumors and minimized adverse effects to normal tissues.

Hypoxia-Activated Prodrug Enabling Synchronous Chemotherapy and HIF-1α Downregulation for Tumor Treatment.

The overexpression of HIF-1α in solid tumors due to hypoxia is closely related to drug resistance and consequent treatment failure. Herein, we constructed a hypoxia-activated prodrug named as YC-Dox. This prodrug could be activated under hypoxic conditions and undergo self-immolation to release doxorubicin (Dox) and YC-1 hemisuccinate (YCH-1), which could execute chemotherapy and result in HIF-1α downregulation, respectively.

Activatable Mitochondria-Targeting Organoarsenic Prodrugs for Bioenergetic Cancer Therapy.

Despite widespread applications for cancer treatment, chemotherapy is restricted by several limitations, including low targeting specificity, acquired drug resistance, and concomitant adverse side effects. It remains challenging to overcome these drawbacks. Herein, we report a new bioenergetic approach for treating cancer efficiently.