RESUMEN
BACKGROUND: Different from Fe ions in Fenton reaction, Mn ions can function both as catalyst for chemodynamic therapy and immune adjuvant for antitumor immune responses. In Mn-mediated Fenton-like reaction, bicarbonate ([Formula: see text]), as the most important component to amplify therapeutic effects, must be present, however, intracellular [Formula: see text] is strictly limited because of the tight control by live cells. RESULTS: Herein, Stimuli-responsive manganese carbonate-indocyanine green complexes (MnCO3-ICG) were designed for intracellular marriage of bicarbonate and Mn ions as "immune ion reactors" to regulate intracellular redox homeostasis and antitumor immune responses. Under the tumor acidic environment, the biodegradable complex can release "ion reactors" of Mn2+ and [Formula: see text], and ICG in the cytoplasm. The suddenly increased [Formula: see text] in situ inside the cells regulate intracellular pH, and accelerate the generation of hydroxyl radicals for the oxidative stress damage of tumors cells because [Formula: see text] play a critical role to catalyze Mn-mediated Fenton-like reaction. Investigations in vitro and in vivo prove that the both CDT and phototherapy combined with Mn2+-enhanced immunotherapy effectively suppress tumor growth and realize complete tumor elimination. CONCLUSIONS: The combination therapy strategy with the help of novel immune adjuvants would produce an enhanced immune response, and be used for the treatment of deep tumors in situ.
Asunto(s)
Bicarbonatos , Neoplasias , Bicarbonatos/uso terapéutico , Línea Celular Tumoral , Homeostasis , Humanos , Inmunidad , Neoplasias/tratamiento farmacológico , Oxidación-ReducciónRESUMEN
Paramagnetic complexes containing gadolinium ions have been widely used for magnetic resonance imaging (MRI) in clinic. However, these paramagnetic complexes pose some safety concerns. There is still a demand for the development of stable MRI contrast agents that exhibit higher sensitivity and superior functionality to existing contrast agents. Here, we develop carbonized paramagnetic complexes of manganese (II) (Mn@CCs) to encapsulate Mn2+ in sealed carbonized shells with superhigh r1 relaxivity. Compared to the most common clinical contrast agent Magnevist, investigations in vivo demonstrate that the Mn@CCs cross the intact blood-brain barrier of normal health mice with minor metal deposition; preferentially target the glioma tissues distribute homogeneously with high penetration in an intracranial mouse model; delineate clear tumor margins in MRIs of ultrasmall single-nodule brain tumors, and multi-nodular liver tumors. The sensitivity, accuracy and low toxicity offer by Mn@CCs provides new opportunities for early molecular diagnostics and imaging-guided biomedical applications.
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Medios de Contraste , Imagen por Resonancia Magnética , Animales , Gadolinio , Iones , Hígado/patología , Imagen por Resonancia Magnética/métodos , Manganeso , RatonesRESUMEN
Background: Asymmetric intracellular and extracellular ionic gradients are critical to the survivability of mammalian cells. Given the importance of manganese (Mn2+), calcium (Ca2+), and bicarbonate (HCO3-) ions, any alteration of the ion-content balance could induce a series of cellular responses. HCO3- plays an indispensable role for Mn-mediated Fenton-like reaction, but this is difficult to achieve because bicarbonates are tightly regulated by live cells, and are limited in anticancer efficacy. Methods: A responsive and biodegradable biomineral, Mn-doped calcium carbonate integrated with dexamethasone phosphate (DEX) (Mn:CaCO3-DEX), was reported to enable synergistic amplification of tumor oxidative stress, reduce inflammation, and induce Ca-overload cell apoptosis by elevating the intracellular and extracellular ionic gradients. Results: Under the acidic environment in tumor region, the ions (Mn2+, CO32-, Ca2+) were released by the degradation of Mn:CaCO3-DEX and then escalated oxidative stresses by triggering a HCO3--indispensable Mn-based Fenton-like reaction and breaking Ca2+ ion homeostasis to cause oxidative stress in cells and calcification. The released anti-inflammatory and antitumor drug, DEX, could alleviate the inflammatory environment. The investigations in vitro and in vivo demonstrated that the synergistic oncotherapy could effectively inhibit the growth of subcutaneous tumors and orthotopic liver tumors. Notably, normal cells showed greater tolerance of the synergistic influences. Conclusion: As an ion drug, Mn:CaCO3-DEX is an excellent potential diagnostic agent for precise orthotopic tumor management by the generation in situ of toxic ion and drug pools in the environment of tumor region, with synergistic effects of enhanced chemodynamic therapy, calcification, and anti-inflammation effects.
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Antineoplásicos/farmacología , Carbonato de Calcio/farmacología , Dexametasona/análogos & derivados , Iones/farmacología , Antineoplásicos/química , Calcio/farmacología , Carbonato de Calcio/química , Línea Celular Tumoral , Dexametasona/química , Dexametasona/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Iones/toxicidad , Manganeso/farmacología , Estrés OxidativoRESUMEN
The therapeutic effect of general photodynamic therapy (PDT) is gravely limited by the poor penetration depth of exogenous light radiation. In recent years, Cerenkov radiation (CR) has been exploringly applied to overcome this critical defect. However, the currently reported type I photosensitizers for CR-induced PDT (CRIT) are only TiO2 nanoparticle-based agents with numerous fatally intrinsic drawbacks. Herein, we developed NH2-Ti32O16 nanocluster (NTOC)-derived ultrasmall nanophotosensitizers (NPSs, denoted as TDPs) via innovate ligand engineering. The introduced dopamine (DA) ligands not only facilitate the water solubility and photocatalytic properties of NPSs but also involve the tumor-targeting behavior through the binding affinity with DA receptors on cancer cells. Under CR irradiation, TDPs enable efficient hydroxyl radical (·OH) generation benefiting from the enhanced separation of hole (h+)-electron (e-) pairs, where the h+ will react with H2O to execute type I PDT and the transferred e- can realize the augmentation of Ti3+ to substantially promote the therapeutic index of chemodynamic therapy. This study provides an easy but feasible strategy for constructing versatile NPSs with an ultrasmall framework structure, propounding a refreshing paradigm for implementing efficient CR-induced combined therapy (CRICT) and spurring the development of CR and titanium-familial nanoplatforms in the fields of photocatalysis and nanocatalytic medicine.
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Antineoplásicos/farmacología , Nanopartículas/química , Óxidos/farmacología , Fotoquimioterapia , Fármacos Fotosensibilizantes/farmacología , Titanio/farmacología , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Partículas beta , Línea Celular , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Humanos , Ligandos , Neoplasias Hepáticas Experimentales/diagnóstico por imagen , Neoplasias Hepáticas Experimentales/tratamiento farmacológico , Neoplasias Hepáticas Experimentales/metabolismo , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Imagen Óptica , Óxidos/química , Fármacos Fotosensibilizantes/síntesis química , Fármacos Fotosensibilizantes/química , Titanio/químicaRESUMEN
X-ray excited persistent luminescence (XEPL) imaging has attracted increasing attention in biomedical imaging due to elimination of autofluorescence, high signal-to-noise ratio and repeatable activation with high penetration. However, optical imaging still suffers from limited for high spatial resolution. Methods: Herein, we report Mn3+-rich manganese oxide (MnOx)-coated chromium-doped zinc gallogermanate (ZGGO) nanoparticles (Mn-ZGGOs). Enhanced XEPL and magnetic resonance (MR) imaging were investigated by the decomposition of MnOx shell in the environment of tumors. We also evaluated the tumor cell-killing mechanism by detection of reactive oxygen (ROS), lipid peroxidation and mitochondrial membrane potential changes in vitro. Furthermore, the in vivo biodistribution, imaging and therapy were studied by U87MG tumor-bearing mice. Results: In the tumor region, the MnOx shell is quickly decomposed to produce Mn3+ and oxygen (O2) to directly generate singlet oxygen (1O2). The resulting Mn2+ transforms endogenous H2O2 into highly toxic hydroxyl radical (·OH) via a Fenton-like reaction. The Mn2+ ions and ZGGOs also exhibit excellent T1-weighted magnetic resonance (MR) imaging and ultrasensitive XEPL imaging in tumors. Conclusion: Both the responsive dual-mode imaging and simultaneous self-supplied O2 for the production of 1O2 and oxygen-independent ·OH in tumors allow for more accurate diagnosis of deep tumors and more efficient inhibition of tumor growth without external activation energy.
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Radical Hidroxilo/metabolismo , Sustancias Luminiscentes , Compuestos de Manganeso , Nanopartículas , Neoplasias Experimentales , Imagen Óptica , Óxidos , Oxígeno Singlete/metabolismo , Animales , Línea Celular Tumoral , Humanos , Sustancias Luminiscentes/química , Sustancias Luminiscentes/farmacocinética , Sustancias Luminiscentes/farmacología , Compuestos de Manganeso/química , Compuestos de Manganeso/farmacocinética , Compuestos de Manganeso/farmacología , Ratones , Nanopartículas/química , Nanopartículas/uso terapéutico , Neoplasias Experimentales/diagnóstico por imagen , Neoplasias Experimentales/tratamiento farmacológico , Neoplasias Experimentales/metabolismo , Óxidos/química , Óxidos/farmacocinética , Óxidos/farmacología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The catalytic activities of currently developed peroxidase-mimic nanozymes are generally limited. Therefore, further efforts are still needed to improve the catalytic performance of peroxidase nanozymes. Herein, we synthesized Fe-coordinated carbon nanozyme dots (Fe-CDs) that can serve as both efficient peroxidase nanozymes and T2-magnetic resonance imaging (MRI) contrast agents. The intrinsic peroxidase-like activity of the Fe-CDs was explored by catalytic oxidation of 3,3',5,5'-tetramethylbenzidine (TMB) with hydrogen peroxide (H2O2). The product showed better performance over natural horseradish peroxidase (HRP) and other mimetic peroxidases. Quantification of glucose and ascorbic acid detection showed that this nanozyme could be used to detect a minimum limit as low as 5 µM glucose. Moreover, the colorimetric detection technique was used to detect serum glucose in mice, and the detection result was comparable with autobiochemistry analyzer results using a glucose assay kit. Furthermore, the Fe-CDs showed good magnetism properties and provided promising MR imaging of tumors with excellent biocompatibility.
Asunto(s)
Carbono , Peroxidasa , Animales , Carbono/química , Colorantes , Medios de Contraste , Glucosa , Peróxido de Hidrógeno/química , Imagen por Resonancia Magnética , Ratones , Peroxidasas/químicaRESUMEN
Light-mediated therapy has many unique merits but monotherapy strategies rarely completely inhibit tumor growth because resistance often develops. Combination therapy is a promising strategy in oncology and has demonstrated superior safety and efficacy over monotherapy. Here, we conjugated a scintillator complex and gold nanorod nanosensitizer for dual-modal image-guided photothermal and X-ray-induced photodynamic therapy (PDT). Lanthanide complexes were successfully conjugated and offer excellent X-ray-excited optical luminescence for PDT effects. The strong near-infrared (NIR) light and X-ray absorption abilities of gold nanorods make the nanosensitizer function as both a photothermal agent for photothermal therapy and a radiosensitizer for enhanced radiotherapy. The studies in vitro and in vivo demonstrated that the nanosensitizer offers good dual-modal imaging capability and significantly suppresses tumor progression under NIR light and X-ray irradiation. This work shows the great potential of conjugating scintillator lanthanide complexes and gold nanosensitizers for multimodal image-guided therapy of deep-seated tumors.