High-precision tumor resection down to few-cell level guided by NIR-IIb molecular fluorescence imaging.

In vivo fluorescence/luminescence imaging in the near-infrared-IIb (NIR-IIb, 1,500 to 1,700 nm) window under <1,000 nm excitation can afford subcentimeter imaging depth without any tissue autofluorescence, promising high-precision intraoperative navigation in the clinic. Here, we developed a compact imager for concurrent visible photographic and NIR-II (1,000 to 3,000 nm) fluorescence imaging for preclinical image-guided surgery. Biocompatible erbium-based rare-earth nanoparticles (ErNPs) with bright down-conversion luminescence in the NIR-IIb window were conjugated to TRC105 antibody for molecular imaging of CD105 angiogenesis markers in 4T1 murine breast tumors. Under a ∼940 ± 38 nm light-emitting diode (LED) excitation, NIR-IIb imaging of 1,500- to 1,700-nm emission afforded noninvasive tumor­to­normal tissue (T/NT) signal ratios of ∼40 before surgery and an ultrahigh intraoperative tumor-to-muscle (T/M) ratio of ∼300, resolving tumor margin unambiguously without interfering background signal from surrounding healthy tissues. High-resolution imaging resolved small numbers of residual cancer cells during surgery, allowing thorough and nonexcessive tumor removal at the few-cell level. NIR-IIb molecular imaging afforded 10-times-higher and 100-times-higher T/NT and T/M ratios, respectively, than imaging with IRDye800CW-TRC105 in the ∼900- to 1,300-nm range. The vastly improved resolution of tumor margin and diminished background open a paradigm of molecular imaging-guided surgery.

The influence of surface charge on the tumor-targeting behavior of Fe3O4 nanoparticles for MRI.

Nanomedicine-based tumor-targeted therapy has emerged as a promising strategy to overcome the lack of specificity of conventional chemotherapeutic agents. "Passive" targeting caused by the tumor EPR effect and "active" targeting endowed by the tumor-targeting moieties provide promising biomedical utilities and cancer therapy strategies for nanomedicine. However, as the nanoparticles are exposed to biological fluids, a large number of protein molecules will be adsorbed on their surface, known as protein corona, which may alter the targeting ability of the nanoparticles. The impact of different protein corona on the "passive" and "active" targeting behaviors is still ambiguous. Herein, three kinds of aqueous soluble Fe3O4 nanoparticles with different surface modifications were synthesized and applied to explore the correlation between their protein corona and passive/active tumor-targeting abilities. In the in vitro and in vivo studies, the protein corona exhibited completely different effects on the active and passive cancer-targeting capability of the particles. The particles presented active cancer-targeting ability if there was enough interaction time between the particles and cells. This was mainly due to the dynamic evolution of the protein corona, the proteins of which may be outcompeted by the cancer cell membrane and determine the targeting abilities. Unfortunately, the protein corona also inevitably accelerated RES/MPS uptake after the particles were injected into the body, which almost completely disabled the active targeting abilities of the particles. We believe that this in-depth understanding of protein corona will provide new ideas on the tumor-targeting mechanisms of nanoparticles and present a feasible approach to designing targeted drugs in the future.

A General Approach to Design Dual Ratiometric Fluorescent and Photoacoustic Probes for Quantitatively Visualizing Tumor Hypoxia Levels In†Vivo.

Herein, we describe an energy balance strategy between fluorescence and photoacoustic effects by sulfur substitution to transform existing hemicyanine dyes (Cy) into optimized NIRF/PA dual ratiometric scaffolds. Based on this optimized scaffold, we reported the first dual-ratio response of nitroreductase probe AS-Cy-NO2 , which allows quantitative visualization of tumor hypoxia in vivo. AS-Cy-NO2 , composed of a new NIRF/PA scaffold thioxanthene-hemicyanine (AS-Cy-1) and a 4-nitrobenzene moiety, showed a 10-fold ratiometric NIRF enhancement (I773 /I733 ) and 2.4-fold ratiometric PA enhancement (PA730 /PA670 ) upon activation by a biomarker (nitroreductase, NTR) associated with tumor hypoxia. Moreover, the dual ratiometric NIRF/PA imaging accurately quantified the hypoxia extent with high sensitivity and high imaging depth in xenograft breast cancer models. More importantly, the 3D maximal intensity projection (MIP) PA images of the probe can precisely differentiate the highly heterogeneous oxygen distribution in solid tumor. Thus, this study provides a promising NIRF/PA scaffold that may be generalized for the dual ratiometric imaging of other disease-relevant biomarkers.

Silencing of Pyruvate Kinase M2 via a Metal-Organic Framework Based Theranostic Gene Nanomedicine for Triple-Negative Breast Cancer Therapy.

Triple-negative breast cancer (TNBC) is typically associated with poor prognosis due to its only partial response to chemotherapy and lack of clinically established targeted therapies coupled with an aggressive disease course. Aerobic glycolysis is a hallmark of reprogrammed metabolic activity in cancer cells, which can be repressed by small-interfering RNA (siRNA). However, the lack of effective carriers to deliver vulnerable siRNA restricts the clinical potentials of glycolysis-based gene therapy for TNBC. Herein, we develop a tumor-targeted, biomimetic manganese dioxide (MnO2)-shrouded metal-organic framework (MOF) based nanomedicine to deliver siRNA against pyruvate kinase muscle isozyme M2 (siPKM2), wherein PKM2 is a rate-limiting enzyme in glycolysis, to inhibit the reprogrammed glycolysis of TNBC. This MOF-based genetic nanomedicine shows excellent monodispersity and stability and protects siPKM2 against degradation by nucleases. The nanomedicine not only substantially blocks the glycolytic pathway but also improves intracellular hypoxia in TNBC cells, with a resultant O2-enhanced anticancer effect. In the mice orthotopic TNBC model, the nanomedicine shows a remarkable therapeutic effect. Meanwhile, the Mn2+ ions released from acid microenvironment-responsive MnO2 enable in vivo monitoring of the therapeutic process with magnetic resonance imaging (MRI). Our study shows great promise with this MRI-visible MOF-based nanomedicine for treating TNBC by inhibition of glycolysis via the RNA interference.

pH-Regulating Nanoplatform for the "Double Channel Chase " of Tumor Cells by the Synergistic Cascade between Chlorine Treatment and Methionine-Depletion Starvation Therapy.

During rapid proliferation and metabolism, tumor cells show a high dependence on methionine. The deficiency of methionine exhibits significant inhibition on tumor growth, which provides a potential therapeutic target in tumor therapy. Herein, ClO2-loaded nanoparticles (fluvastatin sodium&metformin&bupivacaine&ClO2@CaSiO3@MnO2-arginine-glycine-aspatic acid (RGD) (MFBC@CMR) NPs) were prepared for synergistic chlorine treatment and methionine-depletion starvation therapy. After outer layer MnO2 was degraded in the high glutathione (GSH) tumor microenvironment (TME), MFBC@CMR NPs released metformin (Me) to target the mitochondria, thus interfering with the tricarboxylic acid (TCA) cycle and promoting the production of lactate. In addition, released fluvastatin sodium (Flu) by the NPs acted on monocarboxylic acid transporter 4 (MCT4) in the cell membrane to inhibit lactate leakage and induce a decrease of intracellular pH, further prompting the NPs to release chlorine dioxide (ClO2), which then oxidized methionine, inhibited tumor growth, and produced large numbers of Cl- in the cytoplasm. Cl- could enter mitochondria through the voltage-dependent anion channel (VDAC) channel, which was opened by bupivacaine (Bup). The disruption of Cl- homeostasis promotes mitochondrial damage and membrane potential decline, leading to the release of cytochrome C (Cyt-C) and apoptosis inducing factor (AIF) and further inducing cell apoptosis. To sum up, the pH-regulating and ClO2-loaded MFBC@CMR nanoplatform can achieve cascade chlorine treatment and methionine-depletion starvation therapy toward tumor cells, which is of great significance for improving the clinical tumor treatment effect.

Highly Efficient Multifunctional Organic Photosensitizer with Aggregation-Induced Emission for In Vivo Bioimaging and Photodynamic Therapy.

Photosensitizers play a critical role in photodynamic therapy (PDT). Multifunctional organic nanoparticles (NPs) that possess bright fluorescence in aggregates, high singlet oxygen (1O2) quantum yield, near-infrared (NIR) absorption and emission, large Stokes shift, two-photon bioimaging, specific organelle targeting, high PDT efficiency, as well as good biocompatibility and photostability are ideal candidate photosensitizers for image-guided PDT. Due to its enhanced fluorescence and high 1O2 generation efficiency in aggregate states, photosensitizers with aggregation-induced emission (AIE) characteristics have attracted increasing interest in PDT. In this study, a new AIE-active Schiff base 5-(((5-(7-(4-(diphenylamino)phenyl)benzo[c][1,2,5]thiadiazol-4-yl)thiophen-2-yl)methylene)amino)-3-methylthiophene-2,4-dicarbonitrile (TBTDC) based on a D-A-π-A skeleton has been designed and synthesized, and it can be readily encapsulated by Pluronic F-127 to form uniform nanoparticles. TBTDC NPs exhibit bright NIR emission at 825 nm with a Stokes shift up to 300 nm, impressive two-photon bioimaging capability with tissue penetration deep into 300 µm, high 1O2 generation quantum yield (0.552), specific targeting to lysosome, as well as good biocompatibility and photostability. Furthermore, TBTDC NPs present remarkable cytotoxicity for tumor cells and suppression of tumor growth in nude mice through reactive oxygen species generation upon white light irradiation. These results reveal that TBTDC NPs have great potential to become excellent candidates for multifunctional organic photosensitizers for two-photon bioimaging and image-guided PDT and are promising in future clinical applications.

Tumor Microenvironment-Activated Theranostics Nanozymes for Fluorescence Imaging and Enhanced Chemo-Chemodynamic Therapy of Tumors.

Chemodynamic therapy (CDT) is widely explored for tumor-specific therapy by converting endogenous H2O2 to lethal ·OH to destroy cancer cells. However, ·OH scavenging by glutathione (GSH) and insufficient intratumoral H2O2 levels seriously hinder the application of CDT. Herein, we reported the fabrication of copper ion-doped ZIF-8 loaded with gold nanozymes and doxorubicin hydrochloride (DOX) for the chemotherapy and CDT synergistic treatment of tumors with the assistance of tumor microenvironment (TME)-activated fluorescence imaging. The Cu2+-doped ZIF-8 shell was gradually degraded to release DOX and gold nanoclusters responding to the acidic TME. The fluorescence signal of the tumor region was acquired after the quenched fluorescence of the gold nanoclusters by Cu2+ and DOX by aggregation-induced quenching was turned on because of the interaction of GSH with Cu2+ and the release of free DOX. The Cu2+ ions could deplete the GSH via redox reactions and the generated Cu+ could convert internal H2O2 to ·OH for tumor CDT. The chemotherapeutic effect of DOX was strengthened through drug efflux inhibition and drug sensitivity increase due to the consumption of GSH and ·OH burst. Moreover, DOX could raise the level of H2O2 and augment the effect of CDT. In addition, the fluorescent gold nanoclusters not only served as a peroxidase to convert H2O2 to ·OH but also employed as an oxidase to consume GSH, resulting in the amplification of chemotherapy and CDT. This work presents an approach to construct tumor microenvironment-activated theranostic probes without external stimuli and to achieve the tumor elimination through cascade reactions and synergistic treatment.

Boosting Chemodynamic Therapy via a Synergy of Hypothermal Ablation and Oxidation Resistance Reduction.

Chemodynamic therapy (CDT), deemed as a cutting-edge antineoplastic therapeutic tactics, efficaciously suppresses tumors via catalytically yielding hydroxyl radicals (•OH) in tumor regions. Nevertheless, its biomedical applications are often restricted by the limited hydrogen peroxide (H2O2) level and upregulated antioxidant defense. Herein, a versatile nanoreactor is elaborately designed via integrating Cu2-xS and MnO2 for T1-weighted magnetic resonance (MR) imaging-guided CDT, synergistically enhanced through hypothermal ablation and oxidation resistance reduction, thereby displaying splendid antitumor efficiency as well as suppression on pulmonary metastasis. The as-synthesized Cu2-xS@MnO2 nanoreactors afford acid-dependent Cu-based and glutathione (GSH)-activated Mn-based catalytic properties for bimodal CDT. Owing to excellent absorbance at the second near-infrared (NIR-II) window, the Cu2-xS furnishes hypo-photo-thermal therapy (PTT) against tumor growth and ameliorates the catalytic performance for thermal-enhanced CDT. Additionally, MnO2 significantly downregulates GSH and glutathione peroxidase 4, which synergistically boosts CDT via promoting oxidative stress, simultaneously generating Mn2+ for MR contrast improvement and activatable tumor imaging. Therefore, this study proffers a new attempt centered on the collaborative strategy integrating NIR-II hypothermal PTT and synergistically enhanced CDT for tumor eradication.

A pH-sensitive T7 peptide-decorated liposome system for HER2 inhibitor extracellular delivery: an application for the efficient suppression of HER2+ breast cancer.

HER2+ breast cancer is highly aggressive and proliferative even after multiple chemotherapy regimens. At present, the available clinical treatment duration of chemotherapeutic agents is limited by severe toxicity to noncancerous tissues, which are attributed to insufficient targeting. Here, we designed an active-targeted and pH-responsive liposome to improve the treatment. The ideas were as follows: (1) using liposome as a nano-delivery system for HER2 inhibitor (lapatinib; LAP) to reduce the toxicity; (2) modifying the capsule with T7 peptide for specific targeted delivery to the tumor cells, and (3) enabling the capsule with the pH-sensitive ability and triggering sustained drug release at extracellular weakly acidic microenvironment to emerge toxicity in tumors and to improve curative effects. It was found that T7 peptide-modified pH-sensitive liposome (T7-LP) was more effective and safer than free drug and unmodified liposome, and reduced drug-induced side effects and noncancerous toxicity. These results support the application potential of T7-LP in improving the efficacy of LAP in HER2+ breast cancer treatment. It might be a novel LAP formulation as a clinical agent.

Grafting of Gd-DTPA onto MOF-808 to enhance MRI performance for guiding photothermal therapy.

Gd(III) chelates are important T1-weighted contrast agents used in clinical magnetic resonance imaging (MRI), but their low longitudinal relaxivity (r1) results in limited imaging efficiency. In this study, we utilize a geometric confinement strategy to restrict a Gd chelate (Gd-DTPA) within the channels of a porous metal-organic framework material (MOF-808) for increasing its r1 relaxivity. Moreover, the Gd-DTPA-grafted MOF-808 nanoparticles were further surface modified with polyaniline (PANI) to construct an MRI-guided photothermal therapy platform. The resulting Gd-DTPA-MOF-808@PANI shows a high r1 relaxivity of 30.1 mM-1 s-1 (0.5 T), which is 5.4 times higher than that of the commercial contrast agent Magnevist. In vivo experiments revealed that Gd-DTPA-MOF-808@PANI has good T1-weighted contrast performance and can effectively guide photothermal ablation of tumors upon 808 nm laser irradiation. This work may shed some light on the design and preparation of high relaxation rate Gd-based contrast agents for theranostic application via utilization of versatile MOF materials.

Missing-Linker-Assisted Artesunate Delivery by Metal-Organic Frameworks for Synergistic Cancer Treatment.

Clinical translation of artesunate (ATS) as a potent antitumor drug has been obstructed by its rapid degradation and low bioavailability. Herein, we report the development of an ATS nanomedicine through the self-assembly with Mn[Co(CN)6 ]2/3 □1/3 metal-organic frameworks (MOFs) that have hidden missing linkers. The defects in MOFs originating from the missing linkers play a key role in increasing the biological stability and tumor accumulation of ATS. Chlorin e6 (Ce6) and ATS can be co-loaded into MOFs for a synergistic antitumor efficacy. In the presence of intracellular HCO3- , Mn2+ acts as an efficient catalyst to promote the bicarbonate-activated H2 O2 system which oxidizes ATS to generate reactive oxygen species and induce oxidative death to cancer cells. The released [CoIII (CN)6 ] linker undergoes a redox reaction with intracellular glutathione to prevent the scavenging ability of reactive oxygen species, contributing to synergistic chemodynamic therapy of ATS and photodynamic therapy of Ce6. Thus, defect-engineered MOFs with hidden missing linkers hold great promise in advancing the practical use of ATS as an antitumor medicine.

Quantitative analysis of metastatic breast cancer in mice using deep learning on cryo-image data.

Cryo-imaging sections and images a whole mouse and provides ~ 120-GBytes of microscopic 3D color anatomy and fluorescence images, making fully manual analysis of metastases an onerous task. A convolutional neural network (CNN)-based metastases segmentation algorithm included three steps: candidate segmentation, candidate classification, and semi-automatic correction of the classification result. The candidate segmentation generated > 5000 candidates in each of the breast cancer-bearing mice. Random forest classifier with multi-scale CNN features and hand-crafted intensity and morphology features achieved 0.8645 ± 0.0858, 0.9738 ± 0.0074, and 0.9709 ± 0.0182 sensitivity, specificity, and area under the curve (AUC) of the receiver operating characteristic (ROC), with fourfold cross validation. Classification results guided manual correction by an expert with our in-house MATLAB software. Finally, 225, 148, 165, and 344 metastases were identified in the four cancer mice. With CNN-based segmentation, the human intervention time was reduced from > 12 to ~ 2 h. We demonstrated that 4T1 breast cancer metastases spread to the lung, liver, bone, and brain. Assessing the size and distribution of metastases proves the usefulness and robustness of cryo-imaging and our software for evaluating new cancer imaging and therapeutics technologies. Application of the method with only minor modification to a pancreatic metastatic cancer model demonstrated generalizability to other tumor models.

Glycocalixarene with luminescence for Warburg effect-mediated tumor imaging and targeted drug delivery.

Fluorescently labeled calix[4]arene glycoconjugates demonstrate multifunctional potential in both Warburg effect mediated tumor imaging and GLUT1 targeted drug delivery. Nitrobenzoxadiazole and mannose conjugated NBD-Man-CA was found to be selectively recognized by GLUT1 and act as a "molecular carrier" for selective tumor targeting.

Development of an Easily Bioconjugatable Water-Soluble Single-Photon Emission-Computed Tomography/Optical Imaging Bimodal Imaging Probe Based on the aza-BODIPY Fluorophore.

A water-soluble fluorescent aza-BODIPY platform (Wazaby) was prepared and functionalized by a polyazamacrocycle agent and a bioconjugable arm. The resulting fluorescent derivative was characterized and bioconjugated onto a trastuzumab monoclonal antibody as a vector. After bioconjugation, the imaging agent appeared to be stable in serum (>72 h at 37 °C) and specifically labeled HER-2-positive breast tumors slices. The bioconjugate was radiolabeled with [111In] indium and studied in vivo. The developed monomolecular multimodal imaging probe (MOMIP) is water-soluble and chemically and photochemically stable, emits in the near infrared (NIR) region (734 nm in aqueous media), and displays a good quantum yield of fluorescence (around 15%). Single-photon emission-computed tomography and fluorescence imaging have been performed in nude mice bearing HER2-overexpressing HCC1954 human breast cancer xenografts and have evidenced the good tumor targeting of the [111In] In bimodal agent. Finally, the proof of concept of using it as a new tool for fluorescence-guided surgery has been shown.

Integrin αvß6-targeted MR molecular imaging of breast cancer in a xenograft mouse model.

BACKGROUND: The motif RXDLXXL-based nanoprobes allow specific imaging of integrin αvß6, a protein overexpressed during tumorigenesis and tumor progression of various tumors. We applied a novel RXDLXXL-coupled cyclic arginine-glycine-aspartate (RGD) nonapeptide conjugated with ultrasmall superparamagnetic iron oxide nanoparticles (referred to as cFK-9-USPIO) for the application of integrin αvß6-targeted magnetic resonance (MR) molecular imaging for breast cancer. METHODS: A novel MR-targeted nanoprobe, cFK-9-USPIO, was synthesized by conjugating integrin αvß6-targeted peptide cFK-9 to N-amino (-NH2)-modified USPIO nanoparticles via a dehydration esterification reaction. Integrin αvß6-positive mouse breast cancer (4 T1) and integrin αvß6 negative human embryonic kidney 293 (HEK293) cell lines were incubated with cFK-9-AbFlour 647 (blocking group) or cFK-9-USPIO (experimental group), and subsequently imaged using laser scanning confocal microscopy (LSCM) and 3.0 Tesla magnetic resonance imaging (MRI) system. The affinity of cFK-9 targeting αvß6 was analyzed by calculating the mean fluorescent intensity in cells, and the nanoparticle targeting effect was measured by the reduction of T2 values in an in vitro MRI. The in vivo MRI capability of cFK-9-USPIO was investigated in 4 T1 xenograft mouse models. Binding of the targeted nanoparticles to αvß6-positive 4 T1 tumors was determined by ex vivo histopathology. RESULTS: In vitro laser scanning confocal microscopy (LSCM) imaging showed that the difference in fluorescence intensity between the targeting and blocking groups of 4 T1 cells was significantly greater than that in HEK293 cells (P < 0.05). The in vitro MRI demonstrated a more remarkable T2 reduction in 4 T1 cells than in HEK293 cells (P < 0.001). The in vivo MRI of 4 T1 xenograft tumor-bearing nude mice showed significant T2 reduction in tumors compared to controls. Prussian blue staining further confirmed that αvß6 integrin-targeted nanoparticles were specifically accumulated in 4 T1 tumors and notably fewer nanoparticles were detected in 4 T1 tumors of mice injected with control USPIO and HEK293 tumors of mice administered cFK-9-USPIO. CONCLUSIONS: Integrin αvß6-targeted nanoparticles have great potential for use in the detection of αvß6-overexpressed breast cancer with MR molecular imaging.

Exploring photoacoustic spectroscopy-based machine learning together with metabolomics to assess breast tumor progression in a xenograft model ex vivo.

In the current study, a breast tumor xenograft was established in athymic nude mice by subcutaneous injection of the MCF-7 cell line and assessed the tumor progression by photoacoustic spectroscopy combined with machine learning tools. The advancement of breast tumors in nude mice was validated by tumor volume kinetics and histopathology and corresponding image analysis by TissueQuant software compared to controls. The ex vivo tumors in progressive conditions belonging to time points, day 5th, 10th, 15th & 20th, were excited with 281 nm pulsed laser light and recorded the corresponding photoacoustic spectra in time domain. The spectra were then pre-processed, augmented for a 10-fold increase in the data strength, and subjected to wavelet packet transformation for feature extraction and selection using MATLAB software. In the present study, the top 10 features from all the time point groups under study were selected based on their prediction ranking values using the mRMR algorithm. The chosen features of all the time-point groups were then subjected to multi-class Support Vector Machine (SVM) algorithms for learning and classifying into respective time point groups under study. The analysis demonstrated accuracy values of 95.2%, 99.5%, and 80.3% with SVM- Radial Basis Function (SVM-RBF), SVM-Polynomial & SVM-Linear, respectively. The serum metabolomic levels during tumor progression complemented photoacoustic patterns of tumor progression, depicting breast cancer pathophysiology.

A PDA-DTC/Cu-MnO2 nanoplatform for MR imaging and multi-therapy for triple-negative breast cancer treatment.

Herein, a multi-functional nanoplatform (PDA-DTC/Cu-MnO2) was established, which has been employed for MR imaging-guided multi-therapy (CDT, PTT and chemotherapy) for cancer treatment. The in vitro and in vivo results confirmed that the biocompatible nanoplatform could significantly induce tumor cell death and inhibit tumor growth.

Novel Anthracycline Utorubicin for Cancer Therapy.

Novel anticancer compounds and their precision delivery systems are actively developed to create potent and well-tolerated anticancer therapeutics. Here, we report the synthesis of a novel anthracycline, Utorubicin (UTO), and its preclinical development as an anticancer payload for nanocarriers. Free UTO was significantly more toxic to cultured tumor cell lines than the clinically used anthracycline, doxorubicin. Nanoformulated UTO, encapsulated in polymeric nanovesicles (polymersomes, PS), reduced the viability of cultured malignant cells and this effect was potentiated by functionalization with a tumor-penetrating peptide (TPP). Systemic peptide-guided PS showed preferential accumulation in triple-negative breast tumor xenografts implanted in mice. At the same systemic UTO dose, the highest UTO accumulation in tumor tissue was seen for the TPP-targeted PS, followed by nontargeted PS, and free doxorubicin. Our study suggests potential applications for UTO in the treatment of malignant diseases and encourages further preclinical and clinical studies on UTO as a nanocarrier payload for precision cancer therapy.

Design, synthesis, and evaluation of positron emission tomography/fluorescence dual imaging probes for targeting facilitated glucose transporter 1 (GLUT1).

Increased energy metabolism followed by enhanced glucose consumption is a hallmark of cancer. Most cancer cells show overexpression of facilitated hexose transporter GLUT1, including breast cancer. GLUT1 is the main transporter for 2-deoxy-2-[18F]fluoro-d-glucose (2-[18F]FDG), the gold standard of positron emission tomography (PET) imaging in oncology. The present study's goal was to develop novel glucose-based dual imaging probes for their use in tandem PET and fluorescence (Fl) imaging. A glucosamine scaffold tagged with a fluorophore and an 18F-label should confer selectivity to GLUT1. Out of five different compounds, 2-deoxy-2-((7-sulfonylfluoro-2,1,3-benzoxadiazol-4-yl)amino)-d-glucose (2-FBDG) possessed favorable fluorescent properties and a similar potency as 2-deoxy-2-((7-nitro-2,1,3-benzoxadiazol-4-yl)amino)-d-glucose (2-NBDG) in competing for GLUT1 transport against 2-[18F]FDG in breast cancer cells. Radiolabeling with 18F was achieved through the synthesis of prosthetic group 7-fluoro-2,1,3-benzoxadiazole-4-sulfonyl [18F]fluoride ([18F]FBDF) followed by the reaction with glucosamine. The radiotracer was finally analyzed in vivo in a breast cancer xenograft model and compared to 2-[18F]FDG. Despite favourable in vitro fluorescence imaging properties, 2-[18F]FBDG was found to lack metabolic stability in vivo, resulting in radiodefluorination. Glucose-based 2-[18F]FBDG represents a novel dual-probe for GLUT1 imaging using FI and PET with the potential for further structural optimization for improved metabolic stability in vivo.

Discovery of novel potent migrastatic Thiazolo[5,4-b]pyridines targeting Lysyl-tRNA synthetase (KRS) for treatment of Cancer metastasis.

Recently, non-canonical roles of Lysyl-tRNA Synthetase (KRS), which is associated with cell migration and cancer metastasis, have been reported. Therefore, KRS has emerged as a promising target for the treatment of cell migration-related diseases, especially cancer metastasis, although the satisfying chemical inhibitors targeting KRS have not yet been identified. Here, we report the discovery of novel, mechanistically unique, and potent cell migration inhibitors targeting KRS, including the chemical and biological studies on the most effective N,N-dialkylthiazolo [5,4-b]pyridin-2-amine (SL-1910). SL-1910 exhibited highly potent migration inhibition (EC50 = 81 nM against the mutant KRS-overexpressed MDA-MB-231 cells) and was superior to the previously reported KRS inhibitor (migration inhibitory EC50 = 8.5 µM against H226 cells). The KRS protein binding study via fluorescence-based binding titration and KRS protein 2D-NMR mapping study, in vitro concentration-dependent cell migration inhibition, and in vivo anti-metastatic activity of SL-1910, which consists of a new scaffold, have been reported in this study. In addition, in vitro absorption, distribution, metabolism, and excretion studies and mouse pharmacokinetics experiments for SL-1910 were conducted.