RESUMEN
Immunotherapy has revolutionized the cancer treatment paradigm, yet efficient immunotherapeutic responses against immune-cold/desert cancers remain challenging. Herein, we report that photoactivatable nanoagonists yield a potent antitumor synergy of photoimmunotherapy against pancreatic ductal adenocarcinoma (PDAC). The nanoagonist was fabricated by assembling an amphiphilic boron dipyrromethene-derived polymer conjugated with a Toll-like receptor agonist via a photocleavable linker and stimulator of interferon genes agonist. The nanoagonist enables light-induced generation of reactive oxygen species and on-demand release of the agonists to yield synergistic photoimmunotherapy. The produced tumor antigens promote dendritic cell maturation, which is further amplified by these agonists for eliciting adaptive immunity, accompanied by apparently abscopal and long-term memory effects. The nanoagonist further alleviates the fibrosis of tumor stroma and the immunosuppressive microenvironment, leading to the deep infiltrations of clinically used therapeutics and immune cells to yield preferable combinational treatments against PDAC models. These results provide valuable insights into activatable nanoparticles for cancer therapy against immune-desert cancers.
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Effective clinical practice of precise photodynamic therapy (PDT) is severely impeded by the inherent drawbacks and aggregation propensity of conventional photosensitizers. An all-in-one approach is highly desired to optimize structural features, photophysical properties, and pharmacokinetic behaviors of photosensitizers. Herein, we have fabricated mesoporous boron dipyrromethene-bridged coordination polymer nanophotosensitizers (BCP-NPs) for high-performance PDT via a unique solvent-assisted assembly strategy. Distinctive photophysical and structural characteristics of BCP-NPs confer enhanced photodynamic activities, together with high cellular uptake and ultrahigh stability. Moreover, BCP-NPs showed excellent tumor accumulation and prolonged tumor retention, achieving eradication of the triple-negative breast cancer (TNBC) model under low-power-density LED irradiation. This work has provided a valuable paradigm for the construction of mesoporous photoactive nanomaterials for biophotonic applications.
Asunto(s)
Nanopartículas , Neoplasias , Fotoquimioterapia , Humanos , Fármacos Fotosensibilizantes/farmacología , Fármacos Fotosensibilizantes/uso terapéutico , Fármacos Fotosensibilizantes/química , Polímeros/química , Nanopartículas/química , Neoplasias/tratamiento farmacológicoRESUMEN
A critical issue in photodynamic therapy (PDT) is inadequate reactive oxygen species (ROS) generation in tumors, causing inevitable survival of tumor cells that usually results in tumor recurrence and metastasis. Existing photosensitizers frequently suffer from relatively low light-to-ROS conversion efficiency with far-red/near-infrared (NIR) light excitation due to low-lying excited states that lead to rapid non-radiative decays. Here, a neutral Ir(III) complex bearing distyryl boron dipyrromethene (BODIPY-Ir) is reported to efficiently produce both ROS and hyperthermia upon far-red light activation for potentiating in vivo tumor suppression through micellization of BODIPY-Ir to form "Micelle-Ir". BODIPY-Ir absorbs strongly at 550-750 nm with a band maximum at 685 nm, and possesses a long-lived triplet excited state with sufficient non-radiative decays. Upon micellization, BODIPY-Ir forms J-type aggregates within Micelle-Ir, which boosts both singlet oxygen generation and the photothermal effect through the high molar extinction coefficient and amplification of light-to-ROS/heat conversion, causing severe cell apoptosis. Bifunctional Micelle-Ir that accumulates in tumors completely destroys orthotopic 4T1 breast tumors via synergistic PDT/photothermal therapy (PTT) damage under light irradiation, and enables remarkable suppression of metastatic nodules in the lungs, together without significant dark cytotoxicity. The present study offers an emerging approach to develop far-red/NIR photosensitizers toward potent cancer therapy.
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Complejos de Coordinación/química , Rayos Infrarrojos , Iridio/química , Micelas , Fotoquimioterapia/métodos , Terapia Fototérmica/métodos , Animales , Compuestos de Boro/química , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/efectos de la radiación , Complejos de Coordinación/farmacología , Complejos de Coordinación/uso terapéutico , Humanos , Ratones , Neoplasias/tratamiento farmacológico , Neoplasias/terapia , Oxígeno Singlete/química , Oxígeno Singlete/metabolismoRESUMEN
Triple-negative breast cancer (TNBC) remains with highest incidence and mortality rates among females, and a critical bottleneck lies in rationally establishing potent therapeutics against TNBC. Here, the self-assembled micellar nanoarchitecture of heavy-atom-modulated supramolecules with efficient cytoplasmic translocation and tunable photoconversion is shown, for potent suppression against primary, metastatic, and recurrent TNBC. Multi-iodinated boron dipyrromethene micelles yield tunable photoconversion into singlet oxygen and a thermal effect, together with deep penetration and subsequent cytoplasmic translocation at the tumor. Tetra-iodinated boron dipyrromethene micelles (4-IBMs) particularly show a distinctly enhanced cooperativity of antitumor efficiency through considerable expressions of apoptotic proteins, potently suppressing subcutaneous, and orthotopic TNBC models, together with reduced oxygen dependence. Furthermore, 4-IBMs yield preferable anti-metastatic and anti-recurrent efficacies through the inhibition of metastasis-relevant proteins, distinct immunogenic cell death, and re-education of M2 macrophages into tumoricidal M1 phenotype as compared to chemotherapy and surgical resection. These results offer insights into the cooperativity of supramolecular nanoarchitectures for potent phototherapy against TNBC.
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Nanomedicina/métodos , Neoplasias de la Mama Triple Negativas/patología , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Femenino , Humanos , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Near-infrared (NIR) light-responsive nanoparticles (NPs) of organic photosensitizers (PS) hold great promise as phototherapeutic agents for precision photoinduced cancer therapy. However, highly photostable PS nanoparticles with extraordinary photoconversion capacities are urgently desired to fully realize potent phototherapy. Here, NIR nonlinear organic chromophore nanoparticles (NOC-NPs) are shown as single-component PS for dually cooperative phototherapy. Upon 785 nm irradiation, excited NOC-NPs pass through intrinsic intramolecular charge transfer (ICT) channel to generate both abundant singlet oxygen and local hyperthermia, affording synergistic photodynamic therapy (PDT) and photothermal therapy (PTT) for tumor ablation. Furthermore, NOC-NPs exhibit dramatic photostability, enhanced cellular uptake, effective cytoplasmic translocation, as well as preferable tumor accumulation, further ensuring favorable in vivo singlet oxygen generation and hyperthermia for photoinduced tumor ablation. Thus, NOC-NPs may represent novel high-performance PS for synergistic photoinduced cancer therapy, providing new insights into the development of potent PS for clinical translation.
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Hipertermia Inducida , Nanopartículas , Neoplasias , Fotoquimioterapia , Línea Celular Tumoral , Humanos , Neoplasias/terapia , FototerapiaRESUMEN
Near-infrared (NIR) light-responsive nanoparticles of organic small-molecule dyes hold great promise as phototherapeutic dyes (PDs) for clinical translation due to their intrinsic merits, including well-defined structure, high purity, and good reproducibility. However, they have been explored with limited success in the development of photostable NIR PDs with extraordinary photoconversion for highly effective phototherapy. Herein, we have described amphiphilic BODIPY dye aggregates within the polymeric micelles (Micelles) as potent bifunctional PDs for dually cooperative phototherapy under NIR irradiation. Micelles possessed an intensive NIR absorption, high photostability, and favorable non-radiative transition, thereby exhibiting both remarkable singlet oxygen generation and photothermal effect under NIR light irradiation. Besides, Micelles had preferable cellular uptake, effective cytoplasmic drug translocation as well as enhanced tumor accumulation. Owing to the combined virtues, Micelles showed clinical potential as bifunctional PDs for photo-induced cancer therapy. This work thus provides a facile strategy to exploit advanced PDs for practical phototherapeutic applications.
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Compuestos de Boro/química , Colorantes/química , Interacciones Hidrofóbicas e Hidrofílicas , Micelas , Fototerapia/métodos , Polímeros/química , Línea Celular , Humanos , Rayos Infrarrojos , Oxígeno Singlete/metabolismoRESUMEN
High-performance photosensitizers are highly desired for achieving selective tumor photoablation in the field of precise cancer therapy. However, photosensitizers frequently suffer from limited tumor suppression or unavoidable tumor regrowth due to the presence of residual tumor cells surviving in phototherapy. A major challenge still remains in exploring an efficient approach to promote dramatic photoconversions of photosensitizers for maximizing the anticancer efficiency. Here, a rational design of boron dipyrromethene (BDP)-based conjugated photosensitizers (CPs) that can induce dually cooperative phototherapy upon light exposure is demonstrated. The conjugated coupling of BDP monomers into dimeric BDP (di-BDP) or trimeric BDP (tri-BDP) induces photoconversions from fluorescence to singlet-to-triplet or nonradiative transitions, together with distinctly redshifted absorption into the near-infrared region. In particular, tri-BDP within nanoparticles shows preferable conversions into both primary thermal effect and minor singlet oxygen upon near-infrared light exposure, dramatically achieving tumor photoablation without any regrowth through their cooperative anticancer efficiency caused by their dominant late apoptosis and moderate early apoptosis. This rational design of CPs can serve as a valuable paradigm for cooperative cancer phototherapy in precision medicine.
RESUMEN
The morphology of 2D cell colonies has been studied to understand tumor metastasis in the past decades. However, 2D cell cultures are lacking many features of 3D tissues, and their physiological behaviors are quite different from solid tumors in vivo. In this work, we studied the multi-cellular tumor spheroid (MCTS) spreading on the substrate, which keeps parts of 3D tissue characteristics and facilitates cell tracking through 2D imaging. By using a high content imaging system (HCS), we tracked multiple spheroids in one single 96-well plate for 36 h. An automated algorithm based on Otsu's method was developed to investigate the morphological details of spheroids through the quantification of radius length and its coefficients of variation. Spheroid spreading is altered by the PIP-platin, which was a novel platinum based drug previously reported by us with an inhibitory effect on cell migration. All parameters showed dose dependent decreases when PIP-platin concentration increased, indicating the inhibition of spheroid expansion by this compound. To investigate the surface roughness of spheroids affected by the drug, we applied the Fourier parameter ß and the normalized standard deviation of the radius STD r / [Formula: see text], which were found inversely proportional to the concentrations of PIP-platin. Particularly at the low drug concentrations, the indices of contour roughness appeared to be more sensitive than spheroid sizes, which could be the potential morphological markers for high content screening of drugs.
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Movimiento Celular , Reconocimiento de Normas Patrones Automatizadas/métodos , Esferoides Celulares/fisiología , Técnicas de Cultivo de Célula , Línea Celular Tumoral , HumanosRESUMEN
Photoactive noble metal nanoparticles are of increasing importance toward personalized cancer therapy in the field of precision nanomedicine. A critical challenge remains in the exploration of clinically potential noble metal nanoparticles for highly efficient cancer theranostics. Here, we introduce albumin-coordinated assembly of clearable Pt nanodots (Pt-NDs) with monodisperse nanostructure as high-performance theranostic agents for imaging-guided photothermal tumor ablation. We precisely manipulate the reduction and growth of tetravalent Pt ions into ultrasmall nanodots through albumin-directed growth kinetics, thereby leading to the synthesis of monodisperse 6.7 nm Pt-NDs with albumin molecules as the corona. Pt-NDs exhibit the surface plasmon resonance at 225 nm with enhanced near-infrared (NIR) absorbance, ideal resistance to photo-bleaching, distinct photoacoustic and X-ray signals, as well as remarkable photothermal effect through non-radiative relaxation under NIR light irradiation. In particular, Pt-NDs possess preferable tumor accumulation, and effective in vivo excretory capability. Thus, these nanodots promote preferable in vivo microscopic photoacoustics and spatially anatomic CT imaging with enhanced contrast, as well as potent hyperthermia-mediated tumor ablation. These findings represent a facile and general approach to fabricate high-performance noble metal nanostructures with clinical potential for cancer theranostics.
Asunto(s)
Albúminas/química , Nanoestructuras/química , Neoplasias/tratamiento farmacológico , Neoplasias/terapia , Fototerapia , Platino (Metal)/uso terapéutico , Nanomedicina Teranóstica , Animales , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Endocitosis/efectos de los fármacos , Fluorescencia , Humanos , Cinética , Ratones Endogámicos BALB C , Ratones Desnudos , Imagen Multimodal , Nanoestructuras/ultraestructura , Neoplasias/patología , Técnicas Fotoacústicas , Platino (Metal)/farmacocinética , Platino (Metal)/farmacología , Distribución Tisular/efectos de los fármacos , Tomografía Computarizada por Rayos XRESUMEN
It is highly desired that satisfactory photoactive agents with ideal photophysical characteristics are explored for potent cancer phototherapeutics. Herein, bifunctional nanoparticles of low-bandgap donor-acceptor (D-A)-type conjugated-polymer nanoparticles (CP-NPs) are developed to afford a highly efficient singlet-to-triplet transition and photothermal conversion for near-infrared (NIR) light-induced photodynamic (PDT)/photothermal (PTT) treatment. CP-NPs display remarkable NIR absorption with the peak at 782 nm, and perfect resistance to photobleaching. Photoexcited CP-NPs undergo singlet-to-triplet intersystem crossing through charge transfer in the excited D-A system and simultaneous nonradiative decay from the electron-deficient electron acceptor isoindigo derivative under single-wavelength NIR light irradiation, leading to distinct singlet oxygen quantum yield and high photothermal conversion efficiency. Moreover, the CP-NPs display effective cellular uptake and cytoplasmic translocation from lysosomes, as well as effective tumor accumulation, thus promoting severe light-triggered damage caused by favorable reactive oxygen species (ROS) generation and potent hyperthermia. Thus, CP-NPs achieve photoactive cell damage through their photoconversion ability for synergistic PDT/PTT treatment with tumor ablation. The proof-of-concept design of D-A-type conjugated-polymer nanoparticles with ideal photophysical characteristics provides a general approach to afford potent photoactive cancer therapy.
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Nanopartículas , Línea Celular Tumoral , Humanos , Neoplasias , PolímerosRESUMEN
Mitochondria-targeted therapy is an alternative strategy for cancer therapy and may overcome the problems of metastasis and drug resistance that usually occur in conventional treatment. In this work, we demonstrate the mitochondria-targeted delivery of a cationic cyclometalated platinum(ii) complex, PIP-platin, in cancer cells. PIP-platin showed selective delivery and accumulation in the mitochondria and exhibited toxicity against a variety of tumor cell lines. The mitochondria were disrupted by PIP-platin, along with the generation of reactive oxygen species, depolarization of mitochondrial membrane potential, release of cytochrome c and necrosis. Interestingly, PIP-platin can promote cell adhesion within several hours and the cells became hard to dislodge from the culture plate. A wound healing assay, transwell migration/invasion assay and 3D spheroid migration assay all demonstrated that PIP-platin can inhibit cell migration/invasion. To illustrate the associated mechanisms, we investigated the intracellular trafficking of ß-catenin, a central protein in the regulation of cell adhesion, and gene transcription for cell proliferation. Upon treatment with PIP-platin, this protein can translocate onto the plasma membrane for increased cell adhesion. In addition, PIP-platin was demonstrated to efficiently inhibit Wnt signaling by blocking the translocation of ß-catenin into the nuclei, thereby preventing cell proliferation. We demonstrate that, accordingly, PIP-platin has remarkable potential for intracellular delivery in mitochondria and has inhibitory effects on cancer cell proliferation and migration/invasion through ß-catenin, and may therefore be exploited as a dual-functional antitumor drug candidate in cancer treatment.
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Neoplasias de la Mama/patología , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Mitocondrias/patología , Platino (Metal)/farmacología , beta Catenina/metabolismo , Células A549 , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Adhesión Celular/efectos de los fármacos , Femenino , Células Hep G2 , Humanos , Ratones , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Invasividad Neoplásica , Platino (Metal)/química , Transducción de Señal/efectos de los fármacos , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Photoconversion tunability of fluorophore dye is of great interest in cancer nanomedicine such as fluorescence imaging, photodynamic therapy (PDT), and photothermal therapy (PTT). Herein, this paper reports wavelength-dependent photoconversional polymeric vesicles of boron dipyrromethene (Bodipy) fluorophore for either PDT under 660 nm irradiation or PTT under 785 nm irradiation. After being assembled within polymeric vesicles at a high drug loading, Bodipy molecules aggregate in the conformations of both J-type and H-type, thereby causing red-shifted absorption into near-infrared region, ultralow radiative transition, and ideal resistance to photobleaching. Such vesicles further possess enhanced blood circulation, preferable tumor accumulation, as well as superior cell uptake as compared to free Bodipy. In particular, the vesicles mainly generate abundant intracellular singlet oxygen for PDT treatment under 660 nm irradiation, while they primarily produce a potent hyperthermia for PTT with tumor ablation through singlet oxygen-synergized photothermal necrosis under 785 nm irradiation. This approach provides a facile and general strategy to tune photoconversion characteristics of fluorophore dyes for wavelength-dependent photoinduced cancer therapy.
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Fotoblanqueo , Línea Celular Tumoral , Humanos , Hipertermia Inducida , Nanomedicina , FotoquimioterapiaRESUMEN
Despite numerous advanced imaging and sterilization techniques available nowadays, the sensitive in vivo diagnosis and complete elimination of drug-resistant bacterial infections remain big challenges. Here we report a strategy to design activatable theranostic nanoprobes against methicillin-resistant Staphylococcus aureus (MRSA) infections. This probe is based on silica nanoparticles coated with vancomycin-modified polyelectrolyte-cypate complexes (SiO2-Cy-Van), which is activated by an interesting phenomenon of bacteria-responsive dissociation of the polyelectrolyte from silica nanoparticles. Due to the aggregation of hydrophobic cypate fluorophores on silica nanoparticles to induce ground-state quenching, the SiO2-Cy-Van nanoprobes are nonfluorescent in aqueous environments. We demonstrate that MRSA can effectively pull out the vancomycin-modified polyelectrolyte-cypate complexes from silica nanoparticles and draw them onto their own surface, changing the state of cypate from off (aggregation) to on (disaggregation) and leading to in vitro MRSA-activated near-infrared fluorescence (NIRF) and photothermal elimination involving bacterial cell wall and membrane disruption. In vivo experiments show that this de novo-designed nanoprobe can selectively enable rapid (4 h postinjection) NIRF imaging with high sensitivity (105 colony-forming units) and efficient photothermal therapy (PTT) of MRSA infections in mice. Remarkably, the SiO2-Cy-Van nanoprobes can also afford a long-term tracking (16 days) of the development of MRSA infections, allowing real-time estimation of bacterial load in infected tissues and further providing a possible way to monitor the efficacy of antimicrobial treatment. The strategy of bacteria-activated polyelectrolyte dissociation from nanoparticles proposed in this work could also be used as a general method for the design and fabrication of bacteria-responsive functional nanomaterials that offer possibilities to combat drug-resistant bacterial infections.
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Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Infecciones Estafilocócicas/terapia , Nanomedicina Teranóstica/métodos , Animales , Antibacterianos/farmacología , Antiinfecciosos/farmacología , Bacterias/efectos de los fármacos , Staphylococcus aureus Resistente a Meticilina/metabolismo , Staphylococcus aureus Resistente a Meticilina/patogenicidad , Ratones , Ratones Endogámicos BALB C , Pruebas de Sensibilidad Microbiana , Células 3T3 NIH , Nanopartículas/uso terapéutico , Dióxido de Silicio/farmacología , Vancomicina/químicaRESUMEN
Protein nanoparticles as nanocarriers are of particular interest in the field of cancer therapy. Nevertheless, so far a facile fabrication of theranostic protein nanoparticles have been explored with limited success for cancer imaging and therapy. In this work, we demonstrate the controllable synthesis of size-tunable Gd2O3@albumin conjugating photosensitizer (PS) (GA-NPs) using hollow albumin as the nanoreactor for magnetic resonance imaging (MRI)-guided photo-induced therapy. The growth of Gd2O3 nanocrystals within the hollow nanoreactors is well regulated through reaction time, and a typical PS (e.g. chlorin e6) is further conjugated with the protein corona of the nanoreactor through facile chemical coupling, followed by the formation of theranostic GA-NPs. GA-NPs exhibit good longitudinal relaxivity, ideal photostability, enhanced cellular uptakes, and preferable size-dependent tumor accumulation. Moreover, GA-NPs effectively generate remarkable photothermal effect, intracellular reactive oxygen species from Ce6, and subsequent cytoplasmic drug translocation, thereby leading to severe synergistic photothermal and photodynamic cell damages. Consequently, GA-NPs exhibit an in vivo size-dependent MRI capacity with enhanced imaging contrast for effective tumor localization, and also generate a potent synergistic photodynamic therapy/photothermal therapy efficacy under irradiation owing to their enhanced tumor accumulation and strong photo-induced cytotoxicity. These results suggest that GA-NPs can act as a promising theranostic protein nanoplatform for cancer imaging and photo-induced therapy.
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Albúminas/administración & dosificación , Gadolinio/administración & dosificación , Imagen por Resonancia Magnética/métodos , Nanopartículas/administración & dosificación , Fotoquimioterapia/métodos , Fármacos Fotosensibilizantes/administración & dosificación , Porfirinas/administración & dosificación , Animales , Neoplasias de la Mama/diagnóstico por imagen , Neoplasias de la Mama/patología , Neoplasias de la Mama/terapia , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Clorofilidas , Hipertermia Inducida/métodos , Ratones , Nanomedicina Teranóstica/métodos , Resultado del TratamientoRESUMEN
Smart nanoparticles are increasingly important in a variety of applications such as cancer therapy. However, it is still a major challenge to develop light-responsive nanoparticles that can maximize the potency of synergistic thermo-chemotherapy under light irradiation. Here, spatially confined cyanine-anchored silica nanochannels loaded with chemotherapeutic doxorubicin (CS-DOX-NCs) for light-driven synergistic cancer therapy are introduced. CS-DOX-NCs possess a J-type aggregation conformation of cyanine dye within the nanochannels and encapsulate doxorubicin through the π-π interaction with cyanine dye. Under near-infrared light irradiation, CS-DOX-NCs produce the enhanced photothermal conversion efficiency through the maximized nonradiative transition of J-type Cypate aggregates, trigger the light-driven drug release through the destabilization of temperature-sensitive π-π interaction, and generate the effective intracellular translocation of doxorubicin from the lysosomes to cytoplasma through reactive oxygen species-mediated lysosomal disruption, thereby causing the potent in vivo hyperthermia and intracellular trafficking of drug into cytoplasma at tumors. Moreover, CS-DOX-NCs possess good resistance to photobleaching and preferable tumor accumulation, facilitating severe photoinduced cell damage, and subsequent synergy between photothermal and chemotherapeutic therapy with tumor ablation. These findings provide new insights of light-driven nanoparticles for synergistic cancer therapy.
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Doxorrubicina/uso terapéutico , Hipertermia Inducida , Indoles/química , Luz , Nanopartículas/química , Propionatos/química , Dióxido de Silicio/química , Animales , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Línea Celular Tumoral , Doxorrubicina/farmacología , Liberación de Fármacos , Endocitosis/efectos de los fármacos , Ratones , Nanopartículas/ultraestructura , Oxígeno Singlete/metabolismo , Distribución Tisular/efectos de los fármacos , Carga Tumoral/efectos de los fármacosRESUMEN
Bifunctional self-assembled nanoparticles with a platinated fluorophore core with ultra-low radiative transition are developed, which can generate both singlet oxygen and the photothermal effect for synergistic photodynamic and photothermal therapy with tumor ablation.
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Nanopartículas del Metal/química , Nanomedicina/métodos , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Fotoquimioterapia , Platino (Metal)/química , Animales , Línea Celular Tumoral , Hipertermia Inducida , Ratones , Oxígeno Singlete/químicaRESUMEN
Chemotherapeutic drugs frequently encounter multiple drug resistance in the field of cancer therapy. The strategy has been explored with limited success for the ablation of drug-resistant tumor via intravenous administration. In this work, the rationally designed light-triggered nanoparticles with multipronged physicochemical and biological features are developed to overcome cisplatin resistance via the assembly of Pt(IV) prodrug and cyanine dye (Cypate) within the copolymer for efficient ablation of cisplatin-resistant tumor. The micelles exhibit good photostability, sustained release, preferable tumor accumulation, and enhanced cellular uptake with reduced efflux on both A549 cells and resistant A549R cells. Moreover, near-infrared light not only triggers the photothermal effect of the micelles for remarkable photothermal cytotoxicity, but also leads to the intracellular translocation of the micelles and reduction-activable Pt(IV) prodrug into cytoplasm through the lysosomal disruption, as well as the remarkable inhibition on the expression of a drug-efflux transporter, multidrug resistance-associated protein 1 (MRP1) for further reversal of drug resistance of A549R cells. Consequently, the multipronged effects of light-triggered micelles cause synergistic cytotoxicity against both A549 cells and A549R cells, and thus efficient ablation of cisplatin-resistant tumor without regrowth. The multipronged features of light-triggered micelles represent a versatile synergistic approach for the ablation of resistant tumor in the field of cancer therapy.
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Antineoplásicos/administración & dosificación , Preparaciones de Acción Retardada/química , Colorantes Fluorescentes/química , Indoles/química , Nanopartículas/química , Platino (Metal)/administración & dosificación , Profármacos/administración & dosificación , Propionatos/química , Animales , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Línea Celular Tumoral , Cisplatino/farmacología , Resistencia a Antineoplásicos , Femenino , Humanos , Luz , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Micelas , Nanopartículas/ultraestructura , Neoplasias/tratamiento farmacológico , Platino (Metal)/farmacología , Platino (Metal)/uso terapéutico , Profármacos/farmacología , Profármacos/uso terapéuticoRESUMEN
Smart nanocarriers are of particular interest as nanoscale vehicles of imaging and therapeutic agents in the field of theranostics. Herein, we report dually pH/reduction-responsive terpolymeric vesicles with monodispersive size distribution, which are constructed by assembling acetal- and disulfide-functionalized star terpolymer with near-infrared cyanine dye and anticancer drug. The vesicular nanostructure exhibits multiple theranostic features including on-demand drug releases responding to pH/reduction stimuli, enhanced photothermal conversion efficiency of cyanine dye, and efficient drug translocation from lysosomes to cytoplasma, as well as preferable cellular uptakes and biodistribution. These multiple theranostic features result in ultrahigh-contrast fluorescence imaging and thermo-chemotherapy-synergized tumor ablation. The dually stimuli-responsive vesicles represent a versatile theranostic approach for enhanced cancer imaging and therapy.
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Doxorrubicina/farmacología , Portadores de Fármacos , Verde de Indocianina/farmacología , Neoplasias Mamarias Animales/terapia , Nanoestructuras/uso terapéutico , Imagen Óptica/métodos , Nanomedicina Teranóstica/métodos , Resinas Acrílicas/química , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Línea Celular Tumoral , Doxorrubicina/química , Liberación de Fármacos , Femenino , Colorantes Fluorescentes/química , Colorantes Fluorescentes/farmacología , Concentración de Iones de Hidrógeno , Hipertermia Inducida/métodos , Verde de Indocianina/química , Neoplasias Mamarias Animales/diagnóstico , Neoplasias Mamarias Animales/patología , Ratones , Ratones Desnudos , Nanoestructuras/química , Nanoestructuras/ultraestructura , Oxidación-Reducción , Tamaño de la Partícula , Procesos Fotoquímicos , Poliésteres/química , Polietilenglicoles/química , Oxígeno Singlete/metabolismoRESUMEN
A readily tunable series of non-planar oligo(ethylene glycol)-substituted phosphorescent Pt(II) complexes has been investigated as live cell imaging agents; suitable structural modifications can give good cellular uptake, traceable mitochondria-specific localization and potent cytotoxic characteristics towards HeLa cells.