RESUMEN
The clinical application of photodynamic therapy (PDT) is limited by oxygen-dependence and side effects caused by photosensitizer residues. Photoinitiators based on the H-abstraction reaction can address these challenges because they can generate alkyl radical-killing cells independently of oxygen and undergo rapid bleaching following H-abstraction. Nonetheless, the development of photoinitiators for PDT has been impeded by the absence of effective design strategies. Herein, we have developed aryl-ketone substituted cyanine (ACy-R), the first red-light triggered H-abstraction photoinitiators for hypoxic cancer therapy. These ACy-R molecules inherited the near-infrared absorption of cyanine dye, and aryl-ketone modification imparted H-abstraction capability. Experimental and quantum calculations revealed that modifying the electron-withdrawing groups of the aryl (e.g., ACy-5F) improved the contribution of the O atom to the photon excitation process promoting intersystem crossing and H-abstraction ability. Particularly, ACy-5F rapidly penetrated cells and enriched in the endoplasmic reticulum. Even under severe hypoxia, ACy-5F initiated red-light induced H-abstraction with intracellular biomolecules, inducing necroptosis and ferroptosis. Moreover, ACy-5F was degraded after H-abstraction, thus avoiding the side effects of long-term phototoxicity after therapy. This study not only provides a crucial molecular tool for hypoxic tumors therapy, but also presents a promising strategy for the development of multifunctional photosensitizers and photoinitiators.
RESUMEN
Prodrug is a potential regime to overcome serious adverse events and off-target effects of chemotherapy agents. Among various prodrug activators, hypoxia stands out owing to the generalizability and prominence in tumor micro-environment. However, existing hypoxia activating prodrugs generally face the limitations of stringent structural requirements, the lack of feedback and the singularity of therapeutic modality, which is imputed to the traditional paradigm that recognition groups must be located at the terminus of prodrugs. Herein, a multifunctional nano-prodrug Mal@Cy-NTR-CB has been designed. In this nano-prodrug, a self-destructive tether is introduced to break the mindset, and achieves the activation by hypoxia of chemotherapy based on Chlorambucil (CB), whose efficacy can be augmented and traced by photodynamic therapy (PDT) and fluorescence from Cyanine dyes (Cy). In addition, Maleimide (Mal) carried by the nano-shells can regulate glutathione (GSH) content, preventing 1O2 scavenging, so as to realize PDT sensitization. Experiments demonstrate that Mal@Cy-NTR-CB specifically responds to hypoxic tumors, and achieve synchronous activation, enhancement and feedback of chemotherapy and PDT, inhibiting the tumor growth effectively. This study broadens the design ideas of activatable prodrugs and provides the possibility of multifunctional nano-prodrugs to improve the generalization and prognosis in precision oncology.
Asunto(s)
Nanopartículas , Neoplasias , Fotoquimioterapia , Profármacos , Humanos , Neoplasias/tratamiento farmacológico , Profármacos/química , Medicina de Precisión , Hipoxia/tratamiento farmacológico , Línea Celular Tumoral , Fármacos Fotosensibilizantes/uso terapéutico , Nanopartículas/química , Microambiente TumoralRESUMEN
The regulation of electrostatic electric fields through electrical stimulation is an efficient method to increase the catalytic activity of nanozymes and improve the therapeutic effect of nanozyme catalytic therapy. Piezoelectric materials, which are capable of generating a built-in electric field under ultrasound (US), not only improve the activity of nanozymes but also enable piezoelectric sonodynamic therapy (SDT). In this study, a sonosensitizer based on a Hf-based metal-organic framework (UIO-66) and Au nanoparticles (NPs) was produced. Under US irradiation, UIO-66 can generate a built-in electric field inside the materials, which promotes electron-hole separation and produces reactive oxygen species (ROS). The introduction of Au NPs facilitated the electron transfer, which inhibited the recombination of the electron-hole pairs and improved the piezoelectric properties of UIO-66. The value of the piezoelectric constant (d33) increased from 71 to 122 pmV-1 after the deposition of Au NPs. In addition, the intrinsic catalase and peroxidase activities of the Au NPs were increased 2-fold after the stimulation from the built-in electric field induced through US exposure. In vivo and in vitro experiments revealed that the proposed sonosensitizer can kill cancer cells and inhibit tumor growth in mice through the enhanced piezoelectric SDT and nanozyme catalytic therapy. The piezoelectric sensitizer proposed in this work proved to be an efficient candidate that can be used for multiple therapeutic modalities in tumor therapy.
Asunto(s)
Nanopartículas del Metal , Estructuras Metalorgánicas , Neoplasias , Compuestos Organometálicos , Terapia por Ultrasonido , Animales , Ratones , Estructuras Metalorgánicas/uso terapéutico , Oro/uso terapéutico , Línea Celular Tumoral , Neoplasias/tratamiento farmacológico , Terapia por Ultrasonido/métodos , Compuestos Organometálicos/uso terapéutico , Especies Reactivas de Oxígeno/uso terapéuticoRESUMEN
BACKGROUND: Calcium ions (Ca2+) participates in various intracellular signal cascades and especially plays a key role in pathways relevant to cancer cells. Mitochondrial metabolism stimulated by calcium overload can trigger the opening of the mitochondrial permeability transition pore (MPTP), which leads to cancer cell death. METHODS: Herein, a mitochondrial pathway for tumour growth inhibition was built via the double-activation of MPTP channel. Fe2+ doped covalent organic frameworks (COF) was synthesised and applied as template to grow CaCO3 shell. Then O2 was storaged into Fe2+ doped COF, forming O2-FeCOF@CaCO3 nanocomposite. After modification with folic acid (FA), O2-FeCOF@CaCO3@FA (OFCCF) can target breast cancer cells and realize PDT/Ca2+ overload synergistic treatment. RESULTS: COF can induce the production of 1O2 under 650 nm irradiation for photodynamic therapy (PDT). Low pH and hypoxia in tumour microenvironment (TME) can activate the nanocomposite to release oxygen and Ca2+. The released O2 can alleviate hypoxia in TME, thus enhancing the efficiency of COF-mediated PDT. Abundant Ca2+ were released and accumulated in cancer cells, resulting in Ca2+ overload. Notably, the reactive oxygen species (ROS) and Ca2+ overload ensure the sustained opening of MPTP, which leads to the change of mitochondria transmembrane potential, the release of cytochrome c (Cyt c) and the activation of caspases 3 for cancer cell apoptosis. CONCLUSION: This multifunctional nanosystem with TME responded abilities provided a novel strategy for innovative clinical cancer therapy.
Asunto(s)
Proteínas de Transporte de Membrana Mitocondrial , Neoplasias , Humanos , Calcio/metabolismo , Hipoxia/metabolismo , Poro de Transición de la Permeabilidad Mitocondrial , Neoplasias/tratamiento farmacológico , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Porphyrin-incorporating covalent organic frameworks were synthesized at room temperature. The resulting products with uniform morphology and excellent crystallinity exhibited good singlet oxygen generation ability. Both in vitro and in vivo experiments demonstrated the significant antitumor efficiency via sonodynamic therapy.
Asunto(s)
Antineoplásicos/farmacología , Estructuras Metalorgánicas/farmacología , Neoplasias/terapia , Porfirinas/farmacología , Terapia por Ultrasonido , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Estructuras Metalorgánicas/síntesis química , Estructuras Metalorgánicas/química , Ratones , Estructura Molecular , Neoplasias/metabolismo , Neoplasias/patología , Imagen Óptica , Tamaño de la Partícula , Porfirinas/química , Oxígeno Singlete/química , Oxígeno Singlete/metabolismo , TemperaturaRESUMEN
Fe2+-baicalein-polyethylene glycol (Fe-BaP) nanoparticles were synthesized by a room temperature wet chemical method via coordination between Fe2+ and baicalein. Fe-BaP possessed high photothermal conversion efficiency (η = 45.6%) and excellent antitumor efficacy was achieved with the synergistic photothermal/chemodynamic tumor therapy.
Asunto(s)
Antineoplásicos/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Compuestos Férricos/farmacología , Compuestos Ferrosos/farmacología , Flavanonas/farmacología , Nanopartículas/química , Terapia Fototérmica , Animales , Antineoplásicos/química , Neoplasias de la Mama/patología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Compuestos Férricos/química , Compuestos Ferrosos/química , Flavanonas/química , Neoplasias Mamarias Experimentales/tratamiento farmacológico , Neoplasias Mamarias Experimentales/patología , Ratones , Tamaño de la Partícula , Polietilenglicoles/química , Polietilenglicoles/farmacologíaRESUMEN
Sonodynamic therapy (SDT) has attracted wide attention for its high tissue-penetration depth capacity. However, developing new kinds of sonosensitizers that are capable of generating large amounts of reactive oxygen species (ROS) still remains a challenge. Herein, covalent organic framework-titanium oxide nanoparticles (COF-TiO2 NPs) were successfully synthesized by using COF as a template. Under ultrasound (US) irradiation, large quantities of ROS can be generated, and compared with pure TiO2 NPs, the SDT performance of COF-TiO2 nanoparticles was significantly improved due to the narrower band gap. Both in vitro and in vivo experiments demonstrated the great tumor inhibitory effect via COF-TiO2-mediated SDT. This work broadens the biomedical applications of COF-based composites.
Asunto(s)
Estructuras Metalorgánicas/química , Nanocompuestos/química , Titanio/química , Terapia por Ultrasonido , Línea Celular Tumoral , HumanosRESUMEN
Ultrasound (US)-induced sonodynamic therapy (SDT) is an efficient and precise method against tumor, and the integration of multiple cancer therapies has been proved as a promising strategy for better therapeutic effects. Herein, for the first time, a multifunctional nanoreactor has been fabricated by integrating Fe-MIL-88B-NH2, PFC-1, and glucose oxidase (GOx) to form urchin-like Fe-MIL-88B-NH2@PFC-1-GOx (MPG) nanoparticles as Fenton's reagent, a sonosensitizer, and a tumor microenvironment (TME) modulator. In detail, MPG can generate â¢OH for chemodynamic therapy (CDT) and deplete glutathione (GSH) to alleviate the antioxidant ability of cancer cells. Moreover, catalase (CAT)-like MPG can react with H2O2 to generate O2 for relieving hypoxia in TME, enhancing GOx-catalyzed glucose oxidation to produce H2O2 and gluconic acid. Then, the regenerated H2O2 can promote the Fenton reaction to achieve GOx catalysis-enhanced CDT. Owing to its large π-electron conjugated system, MPG also serves as an ideal sonosensitizer, realizing a burst generation of 1O2 under US irradiation for efficient SDT. Therefore, the tumor treatment will be notably enhanced by MPG-based synergetic CDT/SDT/starvation therapy via a series of cascade reactions. Overall, this work develops a versatile nanoreactor with improved tumor treatment effectiveness and broadens the application prospects of porous materials in the field of biomedical research.
Asunto(s)
Glucosa Oxidasa/uso terapéutico , Neoplasias Mamarias Animales/terapia , Estructuras Metalorgánicas/uso terapéutico , Nanocompuestos/uso terapéutico , Animales , Biocatálisis , Catálisis , Línea Celular Tumoral , Femenino , Glucosa Oxidasa/química , Glutatión/metabolismo , Enlace de Hidrógeno , Peróxido de Hidrógeno/metabolismo , Neoplasias Mamarias Animales/metabolismo , Neoplasias Mamarias Animales/patología , Estructuras Metalorgánicas/química , Ratones , Ratones Endogámicos BALB C , Modelos Moleculares , Nanocompuestos/química , Nanocompuestos/ultraestructura , Nanomedicina , Hipoxia Tumoral/efectos de los fármacos , Terapia por UltrasonidoRESUMEN
Cancer deaths are mainly caused by tumor metastases. However, tumor ablation therapies can only target the primary tumor but not inhibit tumor metastasis. Herein, a multifunctional covalent organic framework (COF)-based nanocomposite is designed for synergetic photo-, chemodynamic- and immunotherapies. Specifically, the synthesized COF possesses the ability to produce singlet oxygen under the 650 nm laser irradiation. After being metallized with FeCl3, p-phenylenediamine is polymerized on the surface of COF with Fe3+ as the oxidant. The obtained poly(p-phenylenediamine) can be used for photothermal therapy. Meanwhile, the overexpressed H2O2 in the tumor would be further catalyzed and decomposed into hydroxyl radicals (â¢OH) by the Fe3+/Fe2+ redox couple via Fenton reaction. Intriguingly, the increase of temperature caused by photothermal therapy can accelerate the production of â¢OH. Moreover, the tumor-associated antigen induced a robust antitumor immune response and effectively inhibited tumor metastasis in the presence of anti-PD-L1 checkpoint blockade. Such a COF-based multifunctional nanoplatform provides an efficacious treatment strategy for both the primary tumor and tumor metastasis.
Asunto(s)
Antineoplásicos/farmacología , Neoplasias del Colon/tratamiento farmacológico , Inhibidores de Puntos de Control Inmunológico/farmacología , Estructuras Metalorgánicas/farmacología , Nanocompuestos/química , Fármacos Fotosensibilizantes/farmacología , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Antígeno B7-H1/antagonistas & inhibidores , Antígeno B7-H1/metabolismo , Línea Celular Tumoral , Neoplasias del Colon/metabolismo , Neoplasias del Colon/patología , Compuestos Férricos/química , Compuestos Férricos/farmacología , Radical Hidroxilo/análisis , Radical Hidroxilo/metabolismo , Inhibidores de Puntos de Control Inmunológico/síntesis química , Inhibidores de Puntos de Control Inmunológico/química , Inmunoterapia , Estructuras Metalorgánicas/síntesis química , Estructuras Metalorgánicas/química , Ratones , Tamaño de la Partícula , Fenilendiaminas/química , Fenilendiaminas/farmacología , Fotoquimioterapia , Fármacos Fotosensibilizantes/síntesis química , Fármacos Fotosensibilizantes/química , Fototerapia , Propiedades de SuperficieRESUMEN
Due to the specific tumor microenvironment (TME) and immunosuppressive state of cancer cells, conventional antitumor therapies face severe challenges, such as high rates of recurrence and metastasis. Herein, Cu-PPT nanoparticles were synthesized based on copper acetate, p-phenylenediamine, and 5,10,15,20-tetra-(4-aminophenyl)porphyrin via oxidative coupling reaction for the first time, and the resultant product was used for synergistic photothermal therapy (PTT), photodynamic therapy (PDT), and chemodynamic therapy (CDT). The polymer nanoparticles exhibited excellent photodynamic and photothermal effect with a photothermal conversion efficacy of 40.1% under 650 and 808 nm laser irradiation, respectively. Encapsulated Cu(I)/Cu(II) ions permitted Cu-PPT with glutathione (GSH) peroxidase-mimicking, catalase-mimicking, and Fenton-like activity to regulate TME. Depletion of overexpressed GSH would reduce antioxidant capacity, generated O2 could relieve hypoxia for enhancing PDT, and hyperthermia from PTT could promote the yield of ·OH. This multifunctional nanosystem with cascade reactions could inhibit tumor growth and activate immune responses effectively. By further combining with antiprogrammed death-ligand 1 (anti-PD-L1) checkpoint blockade therapy, distant tumor growth and cancer metastasis were successfully suppressed.
Asunto(s)
Cobre/química , Inmunoterapia/métodos , Nanopartículas/química , Fotoquimioterapia/métodos , Polímeros/química , Antígeno B7-H1/inmunología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Proliferación Celular/efectos de la radiación , Humanos , Rayos Láser , Metástasis de la Neoplasia , Porfirinas/químicaRESUMEN
As traditional cancer treatment methods, photodynamic therapy (PDT) and photothermal therapy (PTT) can eliminate primary tumors, but they cannot inhibit extensive tumor metastasis and local recurrence. Herein, in order to prevent intermolecular accumulation and improve photostability, indocyanine green (ICG) is spontaneously adsorbed onto a covalent organic framework (COF) with high affinity through π-π conjugation, and then chicken ovalbumin (OVA) is coated on the surface of COF@ICG via an electrostatic interaction force. The resultant COF@ICG@OVA can ablate primary tumors under 650 nm and 808 nm laser irradiation due to its high photothermal conversion efficiency (η = 35.75%) and ability to produce reactive oxygen species (ROS). Tumor-associated antigens are also produced after combinational PTT/PDT therapy. By further combining with anti-PD-L1 checkpoint blockade therapy, it can effectively eliminate primary tumors and inhibit the metastasis of cancer cells by generating strong immune responses. Taken together, COF@ICG@OVA nanoparticles offer an efficient synergistic therapeutic modality for the treatment of tumor metastasis.
Asunto(s)
Aldehídos/farmacología , Derivados del Benceno/farmacología , Inmunoterapia , Nanopartículas/química , Fototerapia , Aldehídos/síntesis química , Aldehídos/química , Animales , Apoptosis/efectos de los fármacos , Derivados del Benceno/síntesis química , Derivados del Benceno/química , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Pollos , Portadores de Fármacos/química , Portadores de Fármacos/farmacología , Femenino , Verde de Indocianina/química , Verde de Indocianina/farmacología , Rayos Láser , Ratones , Ratones Endogámicos BALB C , Ovalbúmina/química , Tamaño de la Partícula , Propiedades de SuperficieRESUMEN
COF-Ag2Se nanoparticles were successfully synthesized under mild conditions via a cation exchange approach using COF and CuSe as templates. The in vitro and in vivo experiments verified the excellent cancer cell killing effect and antitumor efficacy of COF-Ag2Se nanoparticles via combined photodynamic and photothermal therapy.