RESUMEN
Bioorthogonal pretargeting optical imaging shows the potential for enhanced diagnosis and prognosis. However, the bioorthogonal handles, known for being "always reactive", may engage in reactions at unintended sites with their counterparts, resulting in nonspecific fluorescence activation and diminishing detection specificity. Meanwhile, despite the importance of detecting senescent cancer cells in cancer therapy, current methods mainly rely on common single senescence-associated biomarkers, which lack specificity for differentiating between various types of senescent cells. Herein, we report a dual-locked enzyme-activatable bioorthogonal fluorescence (DEBOF) turn-on imaging approach for the specific detection of senescent cancer cells. A dual-locked bioorthogonal targeting agent (DBTA) and a bioorthogonally activatable fluorescent imaging probe (BAP) are synthesized as the biorthogonal pair. DBTA is a tetrazine derivative dually caged by two enzyme-cleavable moieties, respectively, associated with senescence and cancer, which ensures that its bioorthogonal reactivity ("clickability") is only triggered in the presence of senescent cancer cells. BAP is a fluorophore caged by trans-cyclooctane (TCO), whose fluorescence is only activated upon bioorthogonal reaction between its TCO and the decaged tetrazine of DBTA. As such, the DEBOF imaging approach differentiates senescent cancer cells from nonsenescent cancer cells or other senescent cells, allowing noninvasive tracking of the population fluctuation of senescent cancer cells in the tumor of living mice to guide cancer therapies. This study thus provides a general molecular strategy for biomarker-activatable in vivo bioorthogonal pretargeting imaging with the potential to be applied to other imaging modalities beyond optics.
Asunto(s)
Senescencia Celular , Colorantes Fluorescentes , Imagen Óptica , Humanos , Colorantes Fluorescentes/química , Colorantes Fluorescentes/síntesis química , Animales , Ratones , Línea Celular Tumoral , Neoplasias/diagnóstico por imagen , FluorescenciaRESUMEN
Dual-locked activatable optical probes, leveraging the orthogonal effects of two biomarkers, hold great promise for the specific imaging of biological processes. However, their design approaches are limited to a short-distance energy or charge transfer mechanism, while the signal readout relies on fluorescence, which inevitably suffers from tissue autofluorescence. Herein, we report a long-distance singlet oxygen transfer approach to develop a bienzyme-locked activatable afterglow probe (BAAP) that emits long-lasting self-luminescence without real-time light excitation for the dynamic imaging of an intratumoral granule enzyme. Composed of an immuno-biomarker-activatable singlet oxygen (1O2) donor and a cancer-biomarker-activatable 1O2 acceptor, BAAP is initially nonafterglow. Only in the presence of both immune and cancer biomarkers can 1O2 be generated by the activated donor and subsequently diffuse toward the activated acceptor, resulting in bright near-infrared afterglow with a high signal-to-background ratio and specificity toward an intratumoral granule enzyme. Thus, BAAP allows for real-time tracking of tumor-infiltrating cytotoxic T lymphocytes, enabling the evaluation of cancer immunotherapy and the differentiation of tumor from local inflammation with superb sensitivity and specificity, which are unachievable by single-locked probes. Thus, this study not only presents the first dual-locked afterglow probe but also proposes a new design way toward dual-locked probes via reactive oxygen species transfer processes.
Asunto(s)
Imagen Óptica , Oxígeno Singlete , Oxígeno Singlete/metabolismo , Oxígeno Singlete/química , Humanos , Colorantes Fluorescentes/química , Animales , Ratones , Biomarcadores de Tumor/metabolismo , Línea Celular Tumoral , Neoplasias/diagnóstico por imagenRESUMEN
Eosinophils are important immune effector cells that affect Tâ cell-mediated antitumor immunity. However, the low frequency and restrained activity of eosinophils restricted the outcome of cancer immunotherapies. We herein report an eosinophil-activating semiconducting polymer nanoparticle (SPNe) to improve photodynamic tumor immunogenicity, modulate eosinophil chemotaxis, and reinvigorate T-cell immunity for activated cancer photo-immunotherapy. SPNe comprises an amphiphilic semiconducting polymer and a dipeptidyl peptidase 4 (DPP4) inhibitor sitagliptin via a 1O2-cleavable thioketal linker. Upon localized NIR photoirradiation, SPNe generates 1O2 to elicit immunogenic cell death of tumors and induce specific activation of sitagliptin. The subsequent inhibition of DPP4 increases intratumoral CCL11 levels to promote eosinophil chemotaxis and activation. SPNe-mediated photo-immunotherapy synergized with immune checkpoint blockade greatly promotes tumor infiltration and activation of both eosinophils and Tâ cells, effectively inhibiting tumor growth and metastasis. Thus, this study presents a generic polymeric nanoplatform to modulate specific immune cells for precision cancer immunotherapy.
Asunto(s)
Eosinófilos , Inmunoterapia , Nanopartículas , Polímeros , Nanopartículas/química , Polímeros/química , Polímeros/farmacología , Ratones , Animales , Eosinófilos/efectos de los fármacos , Eosinófilos/metabolismo , Eosinófilos/inmunología , Semiconductores , Humanos , Neoplasias/tratamiento farmacológico , Neoplasias/terapia , Neoplasias/patología , Fotoquimioterapia , Línea Celular Tumoral , Antineoplásicos/química , Antineoplásicos/farmacologíaRESUMEN
Tumor-associated mast cells (TAMCs) have been recently revealed to play a multifaceted role in the tumor microenvironment. Noninvasive optical imaging of TAMCs is thus highly desired to gain insights into their functions in cancer immunotherapy. However, due to the lack of a single enzyme that is specific to mast cells, a common probe design approach based on single-enzyme activation is not applicable. Herein, we reported a bienzyme-locked molecular probe (THCMC) based on a photoinduced electron transfer-intramolecular charge-transfer hybrid strategy for in vivo imaging of TAMCs. The bienzyme-locked activation mechanism ensures that THCMC exclusively turns on near-infrared (NIR) fluorescence only in the presence of both tryptase and chymase specifically coexpressed by mast cells. Thus, THCMC effectively distinguishes mast cells from other leukocytes, including T cells, neutrophils, and macrophages, a capability lacking in single-locked probes. Such a high specificity of THCMC allows noninvasive tracking of the fluctuation of TAMCs in the tumor of living mice during cancer immunotherapy. The results reveal that the decreased intratumoral signal of THCMC after combination immunotherapy correlates well with the reduced population of TAMCs, accurately predicting the inhibition of tumor growth. Thus, this study not only presents the first NIR fluorescent probe specific for TAMCs but also proposes a generic bienzyme-locked probe design approach for in vivo cell imaging.
Asunto(s)
Colorantes Fluorescentes , Mastocitos , Imagen Óptica , Colorantes Fluorescentes/química , Colorantes Fluorescentes/síntesis química , Animales , Ratones , Triptasas/metabolismo , Humanos , Quimasas/metabolismo , Neoplasias/diagnóstico por imagen , Línea Celular TumoralRESUMEN
Although colorectal cancer diagnosed at an early stage shows high curability, methods simultaneously possessing point-of-care testing ability and high sensitivity are limited. Here, an orally deliverable biomarker-activatable probe (termed as HATS) for early detection of orthotopic tumors via remote urinalysis is presented. To enable its oral delivery to the colon, HATS is designed to have remarkable resistance to acidity and digestive enzymes in the stomach and small intestine and negligible intestinal absorption. Upon reaction with a cancer biomarker in the colon segment, HATS releases a small fragment of tetrazine that can transverse the intestinal barrier, enter blood circulation, and ultimately undergo renal clearance to urine. Subsequently, the urinary tetrazine fragment is detected by bioorthogonal reaction with trans-cyclooctene-caged resorufin (TCO-Reso) to afford a rapid and specific fluorescence enhancement of TCO-Reso. Such signal readout is correlated with the urinary tetrazine concentration and thus measures the level of cancer biomarkers in the colon. HATS-based optical urinalysis detects orthotopic colon tumors two weeks earlier than clinical serological tests and can be developed to a point-of-care paper test. Thereby, HATS-based urinalysis provides a non-invasive and sensitive approach to cancer screening at low-resource settings.
Asunto(s)
Biomarcadores de Tumor , Biomarcadores de Tumor/orina , Animales , Ratones , Humanos , Neoplasias Gastrointestinales/diagnóstico , Neoplasias Gastrointestinales/orina , Urinálisis/métodos , Línea Celular Tumoral , Detección Precoz del Cáncer/métodos , Colorantes Fluorescentes/química , Administración OralRESUMEN
Combination cancer immunotherapy based on electromagnetic energy and immunotherapy shows potent anti-cancer efficacy. However, as a factor that mediates tumor metastasis and immune suppression, the impact of tumor exosomes on therapy under electromagnetic energy stimulation remains unclear. Herein, findings indicate that sonodynamic therapy (SDT) increases serum exosome levels by inducing apoptotic exosomes and loosening the tumor extracellular matrix, promoting lung metastasis. To address this problem, an exosome-inhibiting polymeric sonosensitizer (EIPS) selectively inhibiting tumor exosome generation in response to the tumor biomarker is synthesized. EIPS consists of a semiconducting polymer backbone capable of inducing SDT and a poly(ethylene glycol) layer conjugated with a tumor-specific enzyme-responsive exosome inhibitor prodrug. After being cleaved by tumor Cathepsin B, EIPS releases active exosome inhibitors, preventing tumor exosome-mediated immune suppression and lung metastasis. As a result, EIPS elicits robust antitumor effects through the synergistic effect of SDT and tumor exosome inhibition, completely preventing lung metastasis and establishing a long-term immune memory effect. This is the first example showing that combining SDT with tumor-specific exosome inhibition can elicit a potent immune response without the help of typical immune agonists.
Asunto(s)
Exosomas , Inmunoterapia , Neoplasias Pulmonares , Exosomas/metabolismo , Exosomas/química , Animales , Ratones , Línea Celular Tumoral , Humanos , Neoplasias Pulmonares/terapia , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/tratamiento farmacológico , Terapia por Ultrasonido/métodos , Polímeros/química , Polietilenglicoles/química , Neoplasias/terapiaRESUMEN
Tumor-associated macrophages (TAMs) play a role in both pro- and anti-tumor functions; and the targeted polarization from M2 to M1 TAMs has become an effective therapy option. Although detection of M1 TAMs is imperative to assess cancer immunotherapeutic efficacy, existing optical probes suffer from shallow tissue penetration depth and poor specificity toward M1 TAMs. Herein, we report a tandem-locked NIR chemiluminescent (CL) probe for specific detection of M1 TAMs. Through a combined molecular engineering approach via both atomic alternation and introduction of electron-withdrawing groups, near-infrared (NIR) chemiluminophores are screened out to possess record-long emission (over 800â nm), record-high CL quantum yield (2.7 % einstein/mol), and prolonged half-life (7.7â h). Based on an ideal chemiluminophore, the tandem-locked probe (DPDGN) is developed to only activate CL signal in the presence of both tumour (γ-glutamyl transpeptidase) and M1 macrophage biomarkers (nitric oxide). Such a tandem-lock design ensures its high specificity towards M1 macrophages in the tumor microenvironment over those in normal tissues or peripheral blood. Thus, DPDGN permits noninvasive imaging and tracking of M1 TAM in the tumor of living mice during R837 treatment, showing a good correlation with ex vivo methods. This study not only reports a new molecular approach towards highly efficient chemiluminophores but also reveals the first tandem-locked CL probes for enhanced imaging specificity.
Asunto(s)
Macrófagos Asociados a Tumores , Animales , Ratones , Imagen Óptica , Humanos , Sustancias Luminiscentes/química , Mediciones LuminiscentesRESUMEN
Inflammatory bowel disease (IBD) is strongly related to the occurrence of accumulation of toxic reactive oxygen species (ROS), inflammation of the mucosa, and an imbalance of intestinal microbes. However, current treatments largely focus on a single factor, yielding unsatisfactory clinical outcomes. Herein, we report a biocompatible and IBD-targeted metabolic nanoregulator (TMNR) that synergistically regulates cellular and bacterial metabolism. The TMNR comprises a melanin-gallium complex (MNR) encapsulated within a thermosensitive and colitis-targeting hydrogel, all composed of natural and FDA-approved components. The TMNR confers superior broad-spectrum antioxidant properties, effectively scavenging reactive oxygen species (ROS) and blocking inflammatory signaling pathways. The presence of Ga3+ in TMNR selectively disrupts iron metabolism in pathogenic microorganisms due to its structural resemblance to the iron atom. Additionally, incorporating a thermosensitive injectable hydrogel enables targeted delivery of TMNR to inflammatory regions, prolonging their retention time and providing a physical barrier function for optimizing IBD treatment efficacy. Collectively, TMNR effectively modulates the redox balance of inflamed colonic epithelial tissue and disrupts iron metabolism in pathogenic microorganisms, thereby eliminating inflammation and restoring intestinal homeostasis against IBD. Hence, this work presents a comprehensive approach for precise spatiotemporal regulation of the intestinal microenvironmental metabolism for IBD treatment.
Asunto(s)
Enfermedades Inflamatorias del Intestino , Humanos , Especies Reactivas de Oxígeno/metabolismo , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Inflamación/metabolismo , Hidrogeles/farmacología , HierroRESUMEN
Cancer immunotherapy has become a promising method for cancer treatment, bringing hope to advanced cancer patients. However, immune-related adverse events caused by immunotherapy also bring heavy burden to patients. Semiconducting polymer nanoparticles (SPNs) as an emerging nanomaterial with high biocompatibility, can eliminate tumors and induce tumor immunogenic cell death through different therapeutic modalities, including photothermal therapy, photodynamic therapy, and sonodynamic therapy. In addition, SPNs can work as a functional nanocarrier to synergize with a variety of immunomodulators to amplify anti-tumor immune responses. In this review, SPNs-based combination cancer immunotherapy is comprehensively summarized according to the SPNs' therapeutic modalities and the type of loaded immunomodulators. The in-depth understanding of existing SPNs-based therapeutic modalities will hopefully inspire the design of more novel nanomaterials with potent anti-tumor immune effects, and ultimately promote their clinical translation.
Asunto(s)
Nanopartículas , Neoplasias , Técnicas Fotoacústicas , Humanos , Polímeros/uso terapéutico , Semiconductores , Técnicas Fotoacústicas/métodos , Nanopartículas/uso terapéutico , Neoplasias/tratamiento farmacológico , Inmunoterapia , Adyuvantes Inmunológicos/uso terapéutico , Línea Celular TumoralRESUMEN
Afterglow luminescence imaging probes, with long-lived emission after cessation of light excitation, have drawn increasing attention in biomedical imaging field owing to their elimination of autofluorescence. However, current afterglow agents always suffer from an unsatisfactory signal intensity and complex systems consisting of multiple ingredients. To address these issues, this study reports a near-infrared (NIR) afterglow luminophore (TPP-DO) by chemical conjugation of an afterglow substrate and a photosensitizer acting as both an afterglow initiator and an energy relay unit into a single molecule, resulting in an intramolecular energy transfer process to improve the afterglow brightness. The constructed TPP-DO NPs emit a strong NIR afterglow luminescence with a signal intensity of up to 108 â p/s/cm2 /sr at a low concentration of 10â µM and a low irradiation power density of 0.05â W/cm2 , which is almost two orders of magnitude higher than most existing organic afterglow probes. The highly bright NIR afterglow luminescence with minimized background from TPP-DO NPs allows a deep tissue penetration depth ability. Moreover, we develop a GSH-activatable afterglow probe (Q-TPP-DO NPs) for ultrasensitive detection of subcutaneous tumor with the smallest tumor volume of 0.048â mm3 , demonstrating the high potential for early diagnosis and imaging-guided surgical resection of tumors.
Asunto(s)
Nanopartículas , Neoplasias , Humanos , Nanopartículas/química , Diagnóstico por Imagen , Fármacos Fotosensibilizantes/química , LuminiscenciaRESUMEN
Chemotherapy-induced peripheral neuropathy (CIPN) has a high prevalence but is poorly managed for cancer patients due to the lack of reliable and sensitive diagnostic techniques. Molecular optical imaging can provide a noninvasive way for real-time monitoring of CIPN; However, this is not reported, likely due to the absence of optical probes capable of imaging deep into the spinal canal and possessing sufficient sensitivity for minimal dosage through local injection into the dorsal root ganglia. Herein, a near-infrared (NIR) chemiluminophore (MPBD) with a chemiluminescence quantum yield higher than other reported probes is synthesized and a NIR activatable chemiluminescent probe (CalCL) is developed for in vivo imaging of CIPN. CalCL is constructed by caging MPBD with calpain-cleavable peptide moiety while conjugating polyethylene glycol chain to endow water solubility. Due to the deep-tissue penetration of chemiluminescence and specific turn-on response of CalCL toward calpain (a hallmark of CIPN), it allows for sensitive detection of paclitaxel-mediated CIPN in living mice, which is unattainable by fluorescence imaging. This study thus not only develops a highly efficient chemiluminescent probe, but also presents the first optical imaging approach toward high-throughput screening of neurotoxic drugs.
Asunto(s)
Antineoplásicos , Enfermedades del Sistema Nervioso Periférico , Humanos , Ratones , Animales , Luminiscencia , Calpaína/efectos adversos , Enfermedades del Sistema Nervioso Periférico/inducido químicamente , Enfermedades del Sistema Nervioso Periférico/diagnóstico por imagen , Paclitaxel , Antineoplásicos/efectos adversos , Imagen ÓpticaRESUMEN
Molecularly generated light, referred to here as "molecular light", mainly includes bioluminescence, chemiluminescence, and Cerenkov luminescence. Molecular light possesses unique dual features of being both a molecule and a source of light. Its molecular nature enables it to be delivered as molecules to regions deep within the body, overcoming the limitations of natural sunlight and physically generated light sources like lasers and LEDs. Simultaneously, its light properties make it valuable for applications such as imaging, photodynamic therapy, photo-oxidative therapy, and photobiomodulation. In this review article, we provide an updated overview of the diverse applications of molecular light and discuss the strengths and weaknesses of molecular light across various domains. Lastly, we present forward-looking perspectives on the potential of molecular light in the realms of molecular imaging, photobiological mechanisms, therapeutic applications, and photobiomodulation. While some of these perspectives may be considered bold and contentious, our intent is to inspire further innovations in the field of molecular light applications.
Asunto(s)
Fotoquimioterapia , Fotoquimioterapia/métodos , Imagen MolecularRESUMEN
Sono-immunotherapy holds great potential for deep tumor inhibition; however, smart sono-therapeutic agents to simultaneously eliminate 'domestic' tumor cells and regulate the 'community' tumor immune microenvironment have rarely been developed. Herein, we report a spatiotemporally controllable semiconducting iron-chelated nano-metallomodulator (SINM) for hypersensitive sono-metallo-immunotherapy of cancer. SINM consists of a semiconducting polymer (SP) backbone chelating iron ions (Fe3+ ) with thiophene-based Schiff base structure, and a hydrophilic side chain. Upon accumulation in tumors after systemic administration, SINM specifically arouses ferroptosis and M1 macrophage polarization due to its response toward the tumor redox environment; meanwhile, the chelation of Fe3+ enhances the sono-sensitizing effect of SPs, leading to enhanced generation of reactive oxygen species for immunogenic cell death. Such combined sonodynamic metallo-immunotherapy of SINM efficiently ablates deep tumor and spatiotemporally regulates immunophenotypes.
Asunto(s)
Quelantes del Hierro , Neoplasias , Humanos , Quelantes del Hierro/farmacología , Quelantes del Hierro/uso terapéutico , Factores Inmunológicos , Adyuvantes Inmunológicos , Neoplasias/tratamiento farmacológico , Inmunoterapia , Hierro , Línea Celular Tumoral , Microambiente TumoralRESUMEN
X-ray-induced afterglow and radiodynamic therapy tackle the tissue penetration issue of optical imaging and phototherapy. However, inorganic nanophosphors used in this therapy have their radio afterglow dynamic function as always on, limiting the detection specificity and treatment efficacy. Here we report organic luminophores (IDPAs) with near-infrared afterglow and 1O2 production after X-ray irradiation for cancer theranostics. The in vivo radio afterglow of IDPAs is >25.0 times brighter than reported inorganic nanophosphors, whereas the radiodynamic production of 1O2 is >5.7 times higher than commercially available radio sensitizers. The modular structure of IDPAs permits the development of a smart molecular probe that only triggers its radio afterglow dynamic function in the presence of a cancer biomarker. Thus, the probe enables the ultrasensitive detection of a diminutive tumour (0.64 mm) with superb contrast (tumour-to-background ratio of 234) and tumour-specific radiotherapy for brain tumour with molecular precision at low dosage. Our work reveals the molecular guidelines towards organic radio afterglow agents and highlights new opportunities for cancer radio theranostics.
Asunto(s)
Nanopartículas , Neoplasias , Humanos , Sondas Moleculares , Medicina de Precisión , Nanopartículas/química , FototerapiaRESUMEN
Real-time in vivo imaging of RNA can enhance the understanding of physio-pathological processes. However, most nucleic acid-based sensors have poor resistance to nucleases and limited photophysical properties, making them suboptimal for this purpose. To address this, a semiconducting polymer nanospherical nucleic acid probe (SENSE) for transcriptomic imaging of cancer immunity in living mice is developed. SENSE comprises a semiconducting polymer (SP) backbone covalently linked with recognition DNA strands, which are complemented by dye-labeled signal DNA strands. Upon detection of targeted T lymphocyte transcript (Gzmb: granzyme B), the signal strands are released, leading to a fluorescence enhancement correlated to transcript levels with superb sensitivity. The always-on fluorescence of the SP core also serves as an internal reference for tracking SENSE uptake in tumors. Thus, SENSE has the dual-signal channel that enables ratiometric imaging of Gzmb transcripts in the tumor of living mice for evaluating chemo-immunotherapy; moreover, it has demonstrated sensitivity and specificity comparable to flow cytometry and quantitative polymerase chain reaction, yet offering a faster and simpler means of T cell detection in resected tumors. Therefore, SENSE represents a promising tool for in vivo RNA imaging.
Asunto(s)
Nanopartículas , Neoplasias , Animales , Ratones , Polímeros , Transcriptoma , Neoplasias/diagnóstico por imagen , Neoplasias/tratamiento farmacológico , Sondas de Ácido Nucleico , ARN , Imagen Óptica/métodos , ADN , InmunoterapiaRESUMEN
Cytokine therapy mediates the interaction between immune cells and non-immune cells in the tumor microenvironment (TME), forming a promising approach in cancer therapy. However, the dose-dependent adverse effects and non-selective stimulation of cytokines limit their clinical use. We herein report a sonodynamic cytokine nano-immunocomplex (SPNAI ) that specifically activates effector T cells (Teffs) for antitumor immunotherapy. By conjugating anti-interleukin-2 (anti-IL-2) antibodies S4B6 on the semiconducting polymer nanoparticles to afford SPNA , this nanoantibody SPNA can bind with IL-2 to form SPNAI which can block the interaction between IL-2 and regulatory T cells (Tregs), selectively activating Teffs in TME. Moreover, SPNAI generates 1 O2 to trigger immunogenic cell death of cancer cells upon sono-irradiation, which promotes the maturation of dendritic cells and the proliferation of Teffs. This SPNAI -mediated combination sonodynamic immunotherapy thus elevates the ratio of Teffs/Tregs in TME, resulting in inhibition of tumor growth, suppression of lung metastasis and prevention of tumor relapse.
Asunto(s)
Citocinas , Neoplasias , Humanos , Citocinas/metabolismo , Interleucina-2 , Linfocitos T Reguladores/metabolismo , Inmunoterapia/métodos , Neoplasias/tratamiento farmacológico , Microambiente Tumoral , Línea Celular TumoralRESUMEN
Acute renal allograft rejection (ARAR) after kidney transplantation associated with reduced graft survival and eventual graft failure is poorly diagnosed in hospitals. Here, we report the development of Artificial bioMarker Probes (AMPros) for sensitive urinalysis of ARAR in murine models. AMPros spontaneously go to the kidneys after systemic administration, specifically react with the prodromal immune biomarkers to activate their near-infrared fluorescence signals to report cell-mediated rejection, and efficiently undergo renal excretion into urine. Thus, AMPros enable convenient optical urinalysis that detects ARAR prior to histological manifestation of rejection, which is also earlier than current diagnostic methods measuring proinflammatory cytokines and peripheral blood lymphocyte mRNAs. Due to the high kidney specificity, AMPros-based urinalysis discriminates allograft rejection against other non-alloimmune specific diseases, which is unattainable by measurement of serological biomarkers. Such a noninvasive and sensitive urine test holds great promise in continuous monitoring of renal allograft conditions at low resource settings for timely clinical interventions.
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Trasplante de Riñón , Animales , Ratones , Riñón/patología , Biomarcadores/orina , Diagnóstico Precoz , Aloinjertos , Rechazo de Injerto/diagnóstico , Rechazo de Injerto/patología , Rechazo de Injerto/orina , Enfermedad AgudaRESUMEN
Afterglow, an intrinsic phenomenon of persistent luminescence emitted from chemical defects after light irradiation, has shown tremendous promise for applications in bioimaging with an ultra-high signal-to-background ratio (SBR) in vivo. In contrast to inorganic phosphor materials, organic afterglow substrates possess high biocompatibility and structural diversity for the construction of molecular afterglow imaging probes with an ideal intensity, wavelength, and duration for in vivo imaging. In this tutorial review, we aim to introduce the recent advances in molecular afterglow imaging with a comprehensive summary of the reported afterglow substrates and mechanisms. Molecular designs of multicomponent afterglow imaging probes are also introduced with their biomedical applications in disease diagnosis and treatment. Lastly, future perspectives and potential challenges of molecular afterglow imaging in preclinical uses and clinical translations are discussed.
Asunto(s)
Nanopartículas , Nanopartículas/química , Luminiscencia , Imagen MolecularRESUMEN
The efficacy of combination immunotherapy has been limited by tumor specificity and immune-related adverse events (irAEs). Herein, we report the development of polymeric STING pro-agonists (PSPA), whose sono-immunotherapeutic efficacy is activated by sono-irradiation and elevated glutathione (GSH) within the tumor microenvironment (TME). PSPA is composed of sonosensitizers (semiconducting polymer) and STING agonists (MSA-2) via the GSH-activatable linkers. Under sono-irradiation, PSPA serves as a sonosensitizer to generate 1 O2 and induce immunogenic cell death (ICD) of malignant tumor cells. Furthermore, MSA-2 is released specifically in tumor microenvironment with highly expressed GSH, minimizing off-target side effects. The activation of the STING pathway elevates the interferon-ß level and synergizes with SDT to enhance the anti-tumor response. Therefore, this work proposes a universal approach for spatiotemporal regulation of cancer sono-immunotherapy.
Asunto(s)
Glutatión , Neoplasias , Humanos , Muerte Celular Inmunogénica , Inmunoterapia , Polímeros , Microambiente Tumoral , Neoplasias/terapia , Línea Celular TumoralRESUMEN
Sonodynamic therapy (SDT) is a promising non-invasive therapeutic modality to treat deep-seated tumors owing to the good tissue penetration ability and spatiotemporal controllability of ultrasound (US); however, the low sonodynamic activity and potential side effects greatly limit its clinical translation. Cancer immunotherapy that leverages the immune system to fight against cancer has great potential to synergize with SDT for the treatment of cancer with high efficiency and safety. In this review, the convergence of SDT with cancer immunotherapy to exert their merits and break through the limitations of combination cancer sono-immunotherapy are discussed. The focus is on the development and construction of organic materials with high sonodynamic activity and immunotherapeutic efficiency. These organic materials not only induce immunogenic cell death to improve tumor immunogenicity via SDT but also activate antitumor immunity via immuno-oncology drug-mediated immune pathway modulation. The combination of various immuno-oncology drugs with organic sonosensitizers is categorized and discussed along with the prospects and challenges for clinical translation.