Mitochondrial Targeted Cerium Oxide Nanoclusters for Radiation Protection and Promoting Hematopoiesis.

Purpose: Mitochondrial oxidative stress is an important factor in cell apoptosis. Cerium oxide nanomaterials show great potential for scavenging free radicals and simulating superoxide dismutase (SOD) and catalase (CAT) activities. To solve the problem of poor targeting of cerium oxide nanomaterials, we designed albumin-cerium oxide nanoclusters (TPP-PCNLs) that target the modification of mitochondria with triphenyl phosphate (TPP). TPP-PCNLs are expected to simulate the activity of superoxide dismutase, continuously remove reactive oxygen species, and play a lasting role in radiation protection. Methods: First, cerium dioxide nanoclusters (CNLs), polyethylene glycol cerium dioxide nanoclusters (PCNLs), and TPP-PCNLs were characterized in terms of their morphology and size, ultraviolet spectrum, dispersion stability and cellular uptake, and colocalization Subsequently, the anti-radiation effects of TPP-PCNLs were investigated using in vitro and in vivo experiments including cell viability, apoptosis, comet assays, histopathology, and dose reduction factor (DRF). Results: TPP-PCNLs exhibited good stability and biocompatibility. In vitro experiments indicated that TPP-PCNLs could not only target mitochondria excellently but also regulate reactive oxygen species (ROS)levels in whole cells. More importantly, TPP-PCNLs improved the integrity and functionality of mitochondria in irradiated L-02 cells, thereby indirectly eliminating the continuous damage to nuclear DNA caused by mitochondrial oxidative stress. TPP-PCNLs are mainly targeted to the liver, spleen, and other extramedullary hematopoietic organs with a radiation dose reduction factor of 1.30. In vivo experiments showed that TPP-PCNLs effectively improved the survival rate, weight change, hematopoietic function of irradiated animals. Western blot experiments have confirmed that TPP-PCNLs play a role in radiation protection by regulating the mitochondrial apoptotic pathway. Conclusion: TPP-PCNLs play a radiologically protective role by targeting extramedullary hematopoietic organ-liver cells and mitochondria to continuously clear ROS.

Study for Photo-Induced Enhanced Raman Spectroscopy with Laser-Induced Periodic Surface Structures on Lithium Niobate on Insulator.

Femtosecond laser irradiation (FLI) of laser-induced periodic surface structures (LIPSSs) has proven to be an efficient and robust strategy for surface modification in nanoscale. Lithium niobate on insulator (LNOI) retains the excellent optoelectric properties of bulk lithium niobate and features intrinsic roughness and defects, exhibiting promising potential in the applications of surface-enhanced Raman spectroscopy (SERS) and photo-induced enhancement Raman spectroscopy (PIERS). Herein, we proposed a novel LNOI-LIPSSs-AgNPs substrate that exhibited an increased SERS enhancement by a factor of 3.7 relative to that without LIPSSs. More remarkably, with UV pre-irradiation, a PIERS amplification up to 8.1 times in comparison to SERS was achieved. Detailed and comprehensive analyses of the enhancement mechanisms prove the synergy between the electromagnetic mechanism and chemical mechanism. Additionally, the PIERS substrate exhibits advantages of high-fabrication efficiency, long-term stability, excellent detection universality, and multicyclic self-cleaning ability, which may trigger new applications in various branches of analytical science.

Association between visceral adipose tissue and asthma based on the NHANES and Mendelian randomization study.

BACKGROUND: Obesity is a crucial risk factor for asthma. Observational studies have examined the association between abdominal obesity and asthma symptoms. This study aimed to investigate the causal relationship between visceral adipose tissue (VAT) and asthma and its potential as an independent indicator. METHODS: This study utilized data from the National Health and Nutrition Examination Survey spanning 2011-8. Multivariable logistic regression and stratified variable selection were employed to identify associations between asthma and VAT. Moreover, a two-sample Mendelian randomization analysis, using 221 genetic variants as instrumental variables, was conducted to assess this relationship further. RESULTS: Our findings indicated that individuals with higher VAT levels were more likely to develop asthma. Visceral obesity remained a significant risk factor for asthma after adjusting for demographic characteristics. Genetic predictions suggest a positive association between VAT and an elevated risk of asthma (odds ratio [OR] = 1.393, 95% confidence interval [CI]: 1.266-1.534, and P = 1.43E-11). No significant polymorphisms were detected using the Mendelian randomization-Egger intercept test. CONCLUSIONS: This study presents potential evidence supporting the causal role of VAT in asthma development. Furthermore, the findings from the Mendelian randomization analysis further reinforce the relationship between VAT and asthma risk.

A Mitochondria-Targeted Ferroptosis Inducer Activated by Glutathione-Responsive Imaging and Depletion for Triple Negative Breast Cancer Theranostics.

Ferroptosis is a new type of iron-dependent programmed cell death characterized by glutathione (GSH) depletion, selenoprotein glutathione peroxidase 4 (GPX4) inactivation, and lipid peroxides accumulation. Mitochondria, as the main source of intracellular energy supply and reactive oxygen species (ROS) generation, play a central role in oxidative phosphorylation and redox homeostasis. Therefore, targeting cancer-cell mitochondria and attacking redox homeostasis is expected to induce robust ferroptosis-mediated anticancer effects. In this work, a theranostic ferroptosis inducer (IR780-SPhF), which can simultaneously achieve the imaging and therapy of triple-negative breast cancer (TNBC) by targeting mitochondria is presented. It is developed from a mitochondria-targeting small molecule (IR780) with cancer-preferential accumulation, enabling it to react with GSH by nucleophilic substitution, resulting in mitochondrial GSH depletion and redox imbalance. More interestingly, IR780-SPhF exhibits GSH-responsive near-infrared fluorescence emission and photoacoustic imaging characteristics, further facilitating diagnosis and treatment with real-time monitoring of TNBC with a highly elevated GSH level. Both in vitro and in vivo results demonstrate that IR780-SPhF exhibits potent anticancer effect, which is significantly stronger than cyclophosphamide, a classic drug commonly recommended for TNBC patients in clinic. Hence, the reported mitochondria-targeted ferroptosis inducer may represent a promising candidate and a prospective strategy for efficient cancer treatment.

The Use of Hydrogel-Based Materials for Radioprotection.

Major causes of the radiation-induced disease include nuclear accidents, war-related nuclear explosions, and clinical radiotherapy. While certain radioprotective drug or bioactive compounds have been utilized to protect against radiation-induced damage in preclinical and clinical settings, these strategies are hampered by poor efficacy and limited utilization. Hydrogel-based materials are effective carriers capable of enhancing the bioavailability of compounds loaded therein. As they exhibit tunable performance and excellent biocompatibility, hydrogels represent promising tools for the design of novel radioprotective therapeutic strategies. This review provides an overview of common approaches to radioprotective hydrogel preparation, followed by a discussion of the pathogenesis of radiation-induced disease and the current states of research focused on using hydrogels to protect against these diseases. These findings ultimately provide a foundation for discussions of the challenges and future prospects associated with the use of radioprotective hydrogels.

Tantalum-Zirconium Co-Doped Metal-Organic Frameworks Sequentially Sensitize Radio-Radiodynamic-Immunotherapy for Metastatic Osteosarcoma.

Due to radiation resistance and the immunosuppressive microenvironment of metastatic osteosarcoma, novel radiosensitizers that can sensitize radiotherapy (RT) and antitumor immunity synchronously urgently needed. Here, the authors developed a nanoscale metal-organic framework (MOF, named TZM) by co-doping high-atomic elements Ta and Zr as metal nodes and porphyrinic molecules (tetrakis(4-carboxyphenyl)porphyrin (TCPP)) as a photosensitizing ligand. Given the 3D arrays of ultra-small heavy metals, porous TZM serves as an efficient attenuator absorbing X-ray energy and sensitizing hydroxyl radical generation for RT. Ta-Zr co-doping narrowed the highest occupied molecular orbital-lowest unoccupied molecular orbital (HOMO-LUMO) energy gap and exhibited close energy levels between the singlet and triplet photoexcited states, facilitating TZM transfer energy to the photosensitizer TCPP to sensitize singlet oxygen (1 O2 ) generation for radiodynamic therapy (RDT). The sensitized RT-RDT effects of TZM elicit a robust antitumor immune response by inducing immunogenic cell death, promoting dendritic cell maturation, and upregulating programmed cell death protein 1 (PD-L1) expression via the cGAS-STING pathway. Furthermore, a combination of TZM, X-ray, and anti-PD-L1 treatments amplify antitumor immunotherapy and efficiently arrest osteosarcoma growth and metastasis. These results indicate that TZM is a promising radiosensitizer for the synergistic RT and immunotherapy of metastatic osteosarcoma.

Rationally Designed Heptamethine Cyanine Photosensitizers that Amplify Tumor-Specific Endoplasmic Reticulum Stress and Boost Antitumor Immunity.

Cancer phototherapy activates immunogenic cell death (ICD) and elicits a systemic antitumor immune response, which is an emerging approach for tumor treatment. Most available photosensitizers require a combination of immune adjuvants or checkpoint inhibitors to trigger antitumor immunity because of the immunosuppressive tumor microenvironment and the limited phototherapeutic effect. A class of tumor-targeting heptamethine cyanine photosensitizers modified with an endoplasmic reticulum (ER)-targeting group (benzenesulfonamide) are synthesized. Phototherapy of tumor cells markedly amplifies ER stress and promotes tumor antigen release, as the ER is required for protein synthesis, secretion, and transport. More importantly, different electron-donating or -withdrawing substitutions are introduced into benzenesulfonamide to modulate the nonradiative decay pathways through intramolecular charge transfer, including singlet-triplet intersystem crossing (photodynamic effect) and internal thermal conversion (photothermal effect). Thus, a heptamethine cyanine photosensitizer containing a binitro-substituted benzenesulfonamide (ER-Cy-poNO2 ) is identified that preferentially accumulates in the ER of tumor cells. It significantly enhances the phototherapeutic effect by inducing excessive ER stress and robust ICD. Consequently, this small molecular photosensitizer triggers a sufficient antitumor immune response and effectively suppresses the growth of both primary and distant metastatic tumors, whereas no apparent toxicity is observed. This heptamethine cyanine photosensitizer has the potential to enhance cancer-targeted immunotherapy.

Tailoring Multifunctional Small Molecular Photosensitizers to In Vivo Self-Assemble with Albumin to Boost Tumor-Preferential Accumulation, NIR Imaging, and Photodynamic/Photothermal/Immunotherapy.

Cancer immunotherapy has great potential in tumor eradication and metastasis suppression. However, systemic administration of immune adjuvants and inadequate specificity in cancer treatment, lead to restricted therapeutic benefits and potential immune-related side effects in clinical settings. In this report, the synthesis of various lengths of heptamethine cyanine small molecules to act as multifunctional photosensitizers (PS) for tumor-specific accumulation, near-infrared (NIR) fluorescent imaging, and photodynamic/photothermal/immunotherapy is optimized. In particular, it is demonstrated that C8, which contains eight carbons on two N-alkyl side chains, efficiently self-assembles with albumin to form nanosized dye-albumin complexes. This feature facilitates C8 in vivo self-assembly to remarkably improve its water-solubility, NIR fluorescent emission, long-term blood circulation, as well as tumor-specific accumulation. More importantly, C8 not only exhibits a superior phototherapeutic effect on primary tumors, but also elicits secretion of damage associated molecular patterns, cytokine secretion, dendritic cell maturation, and cytotoxic T lymphocytes activation, ultimately triggering a sufficient antitumor immune response to suppress growths of distant and metastatic tumors. Hence, this multifunctional small molecular PS is characterized with excellent tumor-preferential accumulation, imaging-guided laser irradiation, and phototherapy-induced in situ antitumor immune response, providing a prospective future of its use in tumor-targeting immunotherapy.

Design and Synthesis of a Mitochondria-Targeting Radioprotectant for Promoting Skin Wound Healing Combined with Ionizing Radiation Injury.

Wound healing is seriously retarded when combined with ionizing radiation injury, because radiation-induced excessive reactive oxygen species (ROS) profoundly affect cell growth and wound healing. Mitochondria play vital roles not only as cellular energy factories but also as the main source of endogenous ROS, and in this work a mitochondria-targeting radioprotectant (CY-TMP1) is reported for radiation injury-combined wound repair. It was designed, synthesized and screened out from different conjugates between mitochondria-targeting heptamethine cyanine dyes and a peroxidation inhibitor 2,2,6,6-tetramethylpiperidinyloxy (TEMPO). CY-TMP1 specifically accumulated in mitochondria, efficiently mitigated mitochondrial ROS and total intracellular ROS induced by 6 Gy of X-ray ionizing irradiation, thereby exhibiting a notable radioprotective effect. The mechanism study further demonstrated that CY-TMP1 protected mitochondria from radiation-induced injury, including maintaining mitochondrial membrane potential (MMP) and ATP generation, thereby reducing the ratio of cell apoptotic death. Particularly, an in vivo experiment showed that CY-TMP1 could effectively accelerate wound closure of mice after 6 Gy of whole-body ionizing radiation. Immunohistochemical staining further indicated that CY-TMP1 may improve wound repair through angiogenesis and re-epithelialization. Therefore, mitochondria-targeting ROS scavengers may present a feasible strategy to conquer refractory wound combined with radiation injury.

Synthesis of a versatile mitochondria-targeting small molecule for cancer near-infrared fluorescent imaging and radio/photodynamic/photothermal synergistic therapies.

Although as a mainstay modal for cancer treatment, the clinical effect of radiotherapy (RT) does not yet meet the need of cancer patients. Developing tumour-preferential radiosensitizers or combining RT with other treatments has been acknowledged highly necessary to enhance the efficacy of RT. The present study reported a multifunctional bioactive small-molecule (designated as IR-83) simultaneously exhibiting tumour-preferential accumulation, near-infrared imaging and radio/photodynamic/photothermal therapeutic effects. IR-83 was designed and synthesized by introducing 2-nitroimidazole as a radiosensitizer into the framework of heptamethine cyanine dyes inherently with tumour-targeting and photosensitizing effects. As results, IR-83 preferentially accumulated in tumours, suppressed tumour growth and metastasis by integrating radio/photodynamic/photothermal multimodal therapies. Mechanism studies showed that IR-83 accumulated in cancer cell mitochondria, induced excessive reactive oxygen species (ROS), and generated high heat after laser irradiation. On one hand, these phenomena led to mitochondrial dysfunction and a sharp decline in oxidative phosphorylation to lessen tissue oxygen consumption. On the other hand, excessive ROS in mitochondria destroyed the balance of antioxidants and oxidative stress balance by down-regulating the intracellular antioxidant system, and subsequently sensitized ionizing radiation-generated irreversible DNA double-strand breaks. Therefore, this study presented a promising radiosensitizer and a new alternative strategy to enhance RT efficacy via mitochondria-targeting multimodal synergistic treatment.

Applications of smartphone-based near-infrared (NIR) imaging, measurement, and spectroscopy technologies to point-of-care (POC) diagnostics.

The role of point-of-care (POC) diagnostics is important in public health. With the support of smartphones, POC diagnostic technologies can be greatly improved. This opportunity has arisen from not only the large number and fast spread of cell-phones across the world but also their improved imaging/diagnostic functions. As a tool, the smartphone is regarded as part of a compact, portable, and low-cost system for real-time POC, even in areas with few resources. By combining near-infrared (NIR) imaging, measurement, and spectroscopy techniques, pathogens can be detected with high sensitivity. The whole process is rapid, accurate, and low-cost, and will set the future trend for POC diagnostics. In this review, the development of smartphone-based NIR fluorescent imaging technology was described, and the quality and potential of POC applications were discussed.

Synthesis of Mitochondria-Anchored Nitroimidazoles with a Versatile NIR Fluorophore for Hypoxic Tumor-Targeting Imaging and Chemoradiotherapy.

Nitroimidazoles are one of the most common radiosensitizers investigated to combat hypoxia-induced resistance to cancer radiotherapy. However, due to poor selectivity distinguishing cancer cells from normal cells, effective doses of radiosensitization are much closer to the doses of toxicity induced by nitroimidazoles, limiting their clinical application. In this work, a tumor-targeting near-infrared (NIR) cyanine dye (IR-808) was utilized as a targeting ligand and an NIR fluorophore tracer to chemically conjugate with different structures of hypoxia-affinic nitroimidazoles. One of the NIR fluorophore-conjugated nitroimidazoles (808-NM2) was identified to preferentially accumulate in hypoxic tumor cells, sensitively outline the tumor contour, and effectively inhibit tumor growth synergistically by chemotherapy and radiotherapy. More importantly, nitroimidazoles were successfully taken into cancer cell mitochondria via 808-NM2 conjugate to exert the synergistic effect of chemoradiotherapy. Regarding the important roles of mitochondria on cancer cell survival and metastasis under hypoxia, 808-NM2 may be hopeful to fight against hypoxic tumors.

Near-infrared oxidative phosphorylation inhibitor integrates acute myeloid leukemia-targeted imaging and therapy.

Acute myeloid leukemia (AML) is a deadly hematological malignancy with frequent disease relapse. The biggest challenge for AML therapy is the lack of methods to target and kill the heterogeneous leukemia cells, which lead to disease relapse. Here, we describe a near-infrared (NIR) fluorescent dye, IR-26, which preferentially accumulates in the mitochondria of AML cells, depending on the hyperactive glycolysis of malignant cell, and simultaneously impairs oxidative phosphorylation (OXPHOS) to exert targeted therapeutic effects for AML cells. In particular, IR-26 also exhibits potential for real-time monitoring of AML cells with an in vivo flow cytometry (IVFC) system. Therefore, IR-26 represents a novel all-in-one agent for the integration of AML targeting, detection, and therapy, which may help to monitor disease progression and treatment responses, prevent unnecessary delays in administering upfront therapy, and improve therapeutic efficiency to the residual AML cells, which are responsible for disease relapse.

Improvement of obesity-associated disorders by a small-molecule drug targeting mitochondria of adipose tissue macrophages.

Pro-inflammatory activation of adipose tissue macrophages (ATMs) is causally linked to obesity and obesity-associated disorders. A number of studies have demonstrated the crucial role of mitochondrial metabolism in macrophage activation. However, there is a lack of pharmaceutical agents to target the mitochondrial metabolism of ATMs for the treatment of obesity-related diseases. Here, we characterize a near-infrared fluorophore (IR-61) that preferentially accumulates in the mitochondria of ATMs and has a therapeutic effect on diet-induced obesity as well as obesity-associated insulin resistance and fatty liver. IR-61 inhibits the classical activation of ATMs by increasing mitochondrial complex levels and oxidative phosphorylation via the ROS/Akt/Acly pathway. Taken together, our findings indicate that specific enhancement of ATMs oxidative phosphorylation improves chronic inflammation and obesity-related disorders. IR-61 might be an anti-inflammatory agent useful for the treatment of obesity-related diseases by targeting the mitochondria of ATMs.

Mobile Health (mHealth) Viral Diagnostics Enabled with Adaptive Adversarial Learning.

Deep-learning (DL)-based image processing has potential to revolutionize the use of smartphones in mobile health (mHealth) diagnostics of infectious diseases. However, the high variability in cellphone image data acquisition and the common need for large amounts of specialist-annotated images for traditional DL model training may preclude generalizability of smartphone-based diagnostics. Here, we employed adversarial neural networks with conditioning to develop an easily reconfigurable virus diagnostic platform that leverages a dataset of smartphone-taken microfluidic chip photos to rapidly generate image classifiers for different target pathogens on-demand. Adversarial learning was also used to augment this real image dataset by generating 16,000 realistic synthetic microchip images, through style generative adversarial networks (StyleGAN). We used this platform, termed smartphone-based pathogen detection resource multiplier using adversarial networks (SPyDERMAN), to accurately detect different intact viruses in clinical samples and to detect viral nucleic acids through integration with CRISPR diagnostics. We evaluated the performance of the system in detecting five different virus targets using 179 patient samples. The generalizability of the system was confirmed by rapid reconfiguration to detect SARS-CoV-2 antigens in nasal swab samples (n = 62) with 100% accuracy. Overall, the SPyDERMAN system may contribute to epidemic preparedness strategies by providing a platform for smartphone-based diagnostics that can be adapted to a given emerging viral agent within days of work.

Dual-Modal Therapeutic Role of the Lactate Oxidase-Embedded Hierarchical Porous Zeolitic Imidazolate Framework as a Nanocatalyst for Effective Tumor Suppression.

The increasing evidence supports the fact that lactate in the tumor microenvironment (TME) plays a vital role in tumor proliferation, metastasis, and recurrence, which in turn is emerging as one of the most interesting molecular targets for tumor treatment. Here, hierarchical porous zeolitic imidazolate framework-8 (ZIF-8) as the nanocarrier is fabricated to simultaneously load lactate oxidase (LOD) and Fe3O4 nanoparticles (NPs), called LOD & Fe3O4@ZIF-8 NPs (LFZ NPs), for tumor therapy. On one hand, the sharp consumption of lactate in the TME by LOD will change the essential "soil" where tumor cells live so as to suppress tumor rapid growth. On the other hand, hydrogen peroxide (H2O2) is produced in the TME from the oxidation of lactate catalyzed by LOD and subsequently converted to highly toxic hydroxyl radicals (•OH) catalyzed by Fe3O4 NPs via Fenton-like reactions to kill tumor cells. Based on the endogenous catalysis, this dual-modal strategy of tumor therapy based on lactate is simple, safe, and effective, which deserves to be well concerned.

Paper-Cut Flexible Multifunctional Electronics Using MoS2 Nanosheet.

Art and science represent human creativity and rational thinking, respectively. When the two seemingly opposite fields are intertwined, there is always a life-changing spark. In particular, the integration of ancient traditional Chinese art into the latest electronic devices is always been an unexcavated topic. Fabricating two-dimensional material with a tensile strain less than 3% with an ultimate global stretch has been an important problem that plagues the current flexible electronics field. The current research is limited to material in small scale, and it is always necessary to develop and extend large-sized flexible electronic systems. Here, inspired by the traditional Chinese paper-cut structure, we present a highly deformable multifunctional electronic system based on the MoS2 nanosheet. In this work, we first demonstrate how the traditional paper-cut structure can open the view of flexible electronics. In order to obtain a large area of MoS2 with excellent performance, we use a metal-assisted exfoliation method to transfer MoS2, followed by fabricating a field effect transistor to characterize its excellent electrical properties. Two photodetectors and a temperature sensor are produced with good performance. The mechanical simulation proves that the structure has more advantages in stretchability than other typical paper-cut structures. From the experimental and mechanical point of view, it is proved that the device can work stably under high deformation. We finally show that the device has broad application prospects in highly deformed organs, tissues, and joints. These findings set a good example of traditional Chinese culture to guide innovation in the field of electronic devices.

An NIR-Fluorophore-Based Therapeutic Endoplasmic Reticulum Stress Inducer.

The endoplasmic reticulum (ER) stress signaling or unfolded protein response (UPR) is a common feature of many human diseases, including cancer. Excessive activation of ER stress directly induces cell death, holding a new promising strategy for the therapeutic intervention of cancer. Current ER-stress-inducing agents mainly target UPR components or proteasomes, which exert limited treatment efficacy and undesired side effects due to unselective ER stress and poor tumor-specific distribution. In this study, a unique near-infrared (NIR) fluorophore, IR-34, is synthesized and identified to selectively and efficiently trigger tumoricidal ER stress by targeting the mitochondrial protein NDUFS1. IR-34 is demonstrated to specifically accumulate in living cancer cells for tumor NIR imaging and drastically inhibit tumor growth and recurrence without causing apparent toxicity. Thus, this multifunctional NIR fluorophore may represent a novel theranostic agent for tumor imaging-guided treatment and also strengthens the idea that mitochondria could be a useful target for therapeutic ER stress in cancer cells.

Characterization of HIF-1α/Glycolysis Hyperactive Cell Population via Small-Molecule-Based Imaging of Mitochondrial Transporter Activity.

The characterization of cancer stem-like cells (CSCs) has profound implications for elucidating cancer biology and developing treatment strategies. Although surface markers are already used to identify CSCs, the expression of these markers is controversially linked to the phenotypes in different types of tumors and does not represent all functionally relevant of CSCs. Very recently, hyperactive HIF-1α/glycolysis metabolic pathway is recognized as a master regulator of CSCs. In this study, a near-infrared fluorescent small-molecule, IR-780, is identified for the exclusive characterization of human CSCs through the HIF-1α/glycolysis dependent mitochondrial transporter ABCB10's activity. The results identified for the first time that ABCB10 is involved in the preferential uptake of IR-780 in CSCs, which is regulated by HIF-1α via the direct interaction with the binding site of ABCB10 gene promoter region. In addition, IR-780 is demonstrated to conjugate with anticancer drug 5-fluorouracil to act as a potential drug delivery carrier for CSC-targeted therapy. Thus, the studies provide a new rational approach independent of surface markers to characterize CSCs via small-molecule-based imaging of HIF-1α/glycolysis hyperactive metabolic pathway dependent mitochondrial transporter's activity, which holds promise for the further development of CSCs targeted diagnostic and therapeutic strategies.

Identification of a fluorescent small-molecule enhancer for therapeutic autophagy in colorectal cancer by targeting mitochondrial protein translocase TIM44.

OBJECTIVE: As the modulation of autophagic processes can be therapeutically beneficial to cancer treatment, the identification of novel autophagic enhancers is highly anticipated. However, current autophagy-inducing anticancer agents exert undesired side effects owing to their non-specific biodistribution in off-target tissues. This study aims to develop a multifunctional agent to integrate cancer targeting, imaging and therapy and to investigate its mechanism. DESIGN: A series of mitochondria-targeting near-infrared (NIR) fluorophores were synthesised, screened and identified for their autophagy-enhancing activity. The optical properties and biological effects were tested both in vitro and in vivo. The underlying mechanism was investigated using inhibitors, small interfering RNA (siRNA), RNA sequencing, mass spectrometry and human samples. RESULTS: We have screened and identified a new NIR autophagy-enhancer, IR-58, which exhibits significant tumour-selective killing effects. IR-58 preferentially accumulates in the mitochondria of colorectal cancer (CRC) cells and xenografts, a process that is glycolysis-dependent and organic anion transporter polypeptide-dependent. IR-58 kills tumour cells and induces apoptosis via inducing excessive autophagy, which is mediated through the reactive oxygen species (ROS)-Akt-mammalian target of rapamycin (mTOR) pathway. RNA sequencing, mass spectrometry and siRNA interference studies demonstrate that translocase of inner mitochondrial membrane 44 (TIM44)-superoxide dismutase 2 (SOD2) pathway inhibition is responsible for the excessive ROS, autophagy and apoptosis induced by IR-58. TIM44 expression correlates positively with CRC development and poor prognosis in patients. CONCLUSIONS: A novel NIR small-molecule autophagy-enhancer, IR-58, with mitochondria-targeted imaging and therapy capabilities was developed for CRC treatment. Additionally, TIM44 was identified for the first time as a potential oncogene, which plays an important role in autophagy through the TIM44-SOD2-ROS-mTOR pathway.