RESUMO
Artificial enzymes have demonstrated therapeutic benefits against diverse malignant tumors, yet their antitumor potencies are still severely compromised by non-selective catalysis, low atomic-utilization efficiency, and undesired off-target toxicity. Herein, it is reported that peroxidase-like biomineralized copper (II) carbonate hydroxide nanocrystals inside single albumin nanocages (CuCH-NCs) act as a pH-activatable proenzyme to achieve tumor-selective and synergistic chemodynamic/chemo-immunotherapy against aggressive triple-negative breast cancers (TNBCs). These CuCH-NCs show pH-sensitive Cu2+ release, which spontaneously undergoes glutathione (GSH)-mediated reduction into Cu+ species for catalyzing the evolution of H2 O2 into hydroxyl radicals (·OH) in a single-atom-like manner to cause chemodynamic cell injury, and simultaneously activates non-toxic disulfiram to cytotoxic complex for yielding selective chemotherapeutic damage via blocking cell proliferation and amplifying cell apoptosis. CuCH-NCs exhibit considerable tumor-targeting capacity with deep penetration depth, thus affording preferable efficacy against orthotopic breast tumors through synergistic chemodynamic/chemotherapy, together with good in vivo safety. Moreover, CuCH-NCs arouse distinct immunogenic cell death effect and upregulate PD-L1 expression upon disulfiram combination, and thus synergize with anti-PD-L1 antibody to activate adaptive and innate immunities, together with relieving immunosuppression, finally yielding potent antitumor efficacy against both primary and metastatic TNBCs. These results provide insights into smart and high-performance proenzymes for synergistic therapy against aggressive cancers.
Assuntos
Nanopartículas , Neoplasias , Humanos , Precursores Enzimáticos , Cobre , Dissulfiram , Imunoterapia , Glutationa , Concentração de Íons de Hidrogênio , Linhagem Celular Tumoral , Peróxido de Hidrogênio , Microambiente TumoralRESUMO
Glutathione (GSH)-activatable probes hold great promise for in vivo cancer imaging, but are restricted by their dependence on non-selective intracellular GSH enrichment and uncontrollable background noise. Here, a holographically activatable nanoprobe caging manganese tetraoxide is shown for tumor-selective contrast enhancement in magnetic resonance imaging (MRI) through cooperative GSH/albumin-mediated cascade signal amplification in tumors and rapid elimination in normal tissues. Once targeting tumors, the endocytosed nanoprobe effectively senses the lysosomal microenvironment to undergo instantaneous decomposition into Mn2+ with threshold GSH concentration of ≈ 0.12 mm for brightening MRI signals, thus achieving high contrast tumor imaging and flexible monitoring of GSH-relevant cisplatin resistance during chemotherapy. Upon efficient up-regulation of extracellular GSH in tumor via exogenous injection, the relaxivity-silent interstitial nanoprobe remarkably evolves into Mn2+ that are further captured/retained and re-activated into ultrahigh-relaxivity-capable complex by stromal albumin in the tumor, and simultaneously allows the renal clearance of off-targeted nanoprobe in the form of Mn2+ via lymphatic vessels for suppressing background noise to distinguish tiny liver metastasis. These findings demonstrate the concept of holographic tumor activation via both tumor GSH/albumin-mediated cascade signal amplification and simultaneous background suppression for precise tumor malignancy detection, surveillance, and surgical guidance.
Assuntos
Albuminas , Glutationa , Imageamento por Ressonância Magnética , Nanopartículas Metálicas , Sondas Moleculares , Neoplasias , Glutationa/administração & dosagem , Glutationa/farmacocinética , Glutationa/farmacologia , Sondas Moleculares/administração & dosagem , Sondas Moleculares/farmacocinética , Sondas Moleculares/farmacologia , Albuminas/administração & dosagem , Albuminas/farmacocinética , Albuminas/farmacologia , Imageamento por Ressonância Magnética/métodos , Meios de Contraste/administração & dosagem , Meios de Contraste/farmacocinética , Meios de Contraste/farmacologia , Aumento da Imagem/métodos , Holografia/métodos , Neoplasias/diagnóstico por imagem , Neoplasias/metabolismo , Lisossomos/efeitos dos fármacos , Lisossomos/metabolismo , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/fisiologia , Nanopartículas Metálicas/administração & dosagem , Transferrina/administração & dosagem , Transferrina/farmacocinética , Transferrina/farmacologia , Distribuição Tecidual , Células A549 , Humanos , Animais , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Cisplatino/administração & dosagem , Cisplatino/farmacocinética , Cisplatino/farmacologia , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologiaRESUMO
Photosensitizers (PSs) that are directly responsive to X-ray for radiodynamic therapy (RDT) with desirable imaging abilities have great potential applications in cancer therapy. Herein, the cerium (Ce)-doped NaCeF4:Gd,Tb scintillating nanoparticle (ScNP or scintillator) is first reported. Due to the sensitization effect of the Ce ions, Tb ions can emit fluorescence under X-ray irradiation to trigger X-ray excited fluorescence (XEF). Moreover, Ce and Tb ions can absorb the energy of secondary electrons generated by X-ray to produce reactive oxide species (ROS) for RDT. With the intrinsic absorption of X-ray by lanthanide elements, the NaCeF4:Gd,Tb ScNPs also act as a computed tomography (CT) imaging contrast agent and radiosensitizers for radiotherapy (RT) sensitization synchronously. Most importantly, the transverse relaxation time of Gd3+ ions is shortened due to the doping of Ce and Tb ions, leading to the excellent performance of our ScNPs in T2-weighted MR imaging for the first time. Both in vitro and in vivo studies verify that our synthesized ScNPs have good performance in XEF, CT, and T2-weighted MR imaging, and a synchronous RT/RDT is achieved with significant suppression on tumor progression under X-ray irradiation. Importantly, no systemic toxicity is observed after intravenous injection of ScNPs. Our work highlights that ScNPs have potential in multimodal imaging-guided RT/RDT of deep tumors.
Assuntos
Elementos da Série dos Lantanídeos/uso terapêutico , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/terapia , Nanopartículas/uso terapêutico , Fármacos Fotossensibilizantes/uso terapêutico , Células A549 , Animais , Cério/uso terapêutico , Meios de Contraste/uso terapêutico , Humanos , Imageamento por Ressonância Magnética , Camundongos Endogâmicos BALB C , Camundongos Nus , Nanopartículas/ultraestrutura , Imagem Óptica , Fotoquimioterapia , Espécies Reativas de Oxigênio/metabolismo , Tomografia Computadorizada por Raios X , Terapia por Raios XRESUMO
Synergistic phototherapy has the potential to conquer the extreme heterogeneity and complexity of difficult tumors and result in better cancer treatment outcomes than monomodal photodynamic therapy (PDT) or photothermal therapy (PTT). However, the previous approaches to combining PDT and PTT are mainly focused on primary tumor obliteration while neglecting tumor metastasis, which is responsible for about 90% of cancer deaths. It is shown that a combined PDT/PTT approach, based on upconversion-polymer hybrid nanoparticles with surface-loaded chlorin e6 photosensitizer, can enhance primary tumor elimination and elicit antitumor immunity against disseminated tumors. The specifical arrangement of an external upconversion coating over the polymer core ensures adequate photoabsorption by the upconversion nanoparticles for the generation of reactive oxygen species upon single near-infrared light irradiation. Furthermore, it is found that synergistic phototherapy can elicit robust systemic and humoral antitumor immune responses. When combined with immune checkpoint blockades, it can inhibit tumor relapse and metastasis as well as prolong the survival of tumor-bearing mice in two types of tumor metastasis models. This study may establish a new modality for enhancing immunogenic cell death through a synergistic phototherapeutic nanoplatform and extend this strategy to overcome tumor metastasis with an augmented antitumor immune response.
Assuntos
Fatores Imunológicos/química , Fatores Imunológicos/farmacologia , Indóis/química , Indóis/farmacologia , Nanopartículas/química , Polímeros/química , Polímeros/farmacologia , Animais , Cápsulas , Linhagem Celular Tumoral , Camundongos , Metástase Neoplásica , Fototerapia , Polietilenoglicóis/químicaRESUMO
Multifunctional nanotheranostic agents are of particular importance in the field of precise nanomedicine. However, a critical challenge remains in the rational fabrication of monodisperse multicomponent nanoparticles with enhanced multifunctional characteristics for efficient cancer theranostics. Here, a rational and facile synthesis of monodisperse Gd2 O3 /Bi2 S3 hybrid nanodots (Gd/Bi-NDs) is demonstrated as a multifunctional nanotheranostic agent using a albumin nanoreactor for computed tomography (CT)/photoacoustics (PA)/magnetic resonance (MR) imaging and simultaneous photothermal tumor ablation. Two nanoprecipitation reactions in one albumin nanoreactor are simultaneously conducted to generate ultrasmall Gd/Bi-NDs with both orthorhombic Bi2 S3 and cubic Gd2 O3 nanostructures. Their hybrid nanostructure generates distinctly enhanced longitudinal relaxivity in the spatially confined albumin nanocage as compared to monocomponent Gd2 O3 nanodots. Moreover, such hybrid nanodots possess multiple desirable characteristics including superior photobleaching resistance, efficient cellular uptake, preferable tumor accumulation, good in vivo clearance, and negligible acute toxicity, thereby leading to complementary PA/CT/MR imaging with spatial and anatomic characteristics, as well as effective photothermal tumor ablation without regrowth. These results represent a promising approach to fabricate monodisperse multicomponent nanotheranostic agents for efficient cancer theranostics.
Assuntos
Imagem Multimodal/métodos , Nanopartículas/química , Linhagem Celular Tumoral , Humanos , Fototerapia/métodos , Nanomedicina Teranóstica/métodosRESUMO
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.
Assuntos
Albuminas/química , Nanoestruturas/química , Neoplasias/tratamento farmacológico , Neoplasias/terapia , Fototerapia , Platina/uso terapêutico , Nanomedicina Teranóstica , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Endocitose/efeitos dos fármacos , Fluorescência , Humanos , Cinética , Camundongos Endogâmicos BALB C , Camundongos Nus , Imagem Multimodal , Nanoestruturas/ultraestrutura , Neoplasias/patologia , Técnicas Fotoacústicas , Platina/farmacocinética , Platina/farmacologia , Distribuição Tecidual/efeitos dos fármacos , Tomografia Computadorizada por Raios XRESUMO
Elemental tellurium (Te) nanoparticles are increasingly important in a variety of applications such as thermoelectricity, photoconductivity, and piezoelectricity. However, they have been explored with limited success in their biomedical use, and thus a tremendous challenge still exists in the exploration of Te nanoparticles that can treat tumors as an effective anticancer agent. Here, we introduce bifunctional Te nanodots with well-defined nanostructure as an effective anticancer agent for photo-induced synergistic cancer therapy with tumor ablation, which is accomplished using hollow albumin nanocages as a nanoreactor. Under near-infrared light irradiation, Te nanodots can produce effective photothermal conversion, as well as highly reactive oxygen species such as â¢O2- and dismutated â¢OH via a type-I mechanism through direct electron transfer, thereby triggering the potent in vivo hyperthermia and simultaneous intracellular reactive oxygen species at tumors. Moreover, Te nanodots possess perfect resistance to photobleaching, effective cytoplasmic translocation, preferable tumor accumulation, as well as in vivo renal elimination, promoting severe photo-induced cell damage and subsequent synergy between photothermal and photodynamic treatments for tumor ablation. These findings provide the insight of elemental Te nanodots for biomedical research.
Assuntos
Antineoplásicos/química , Neoplasias da Mama/tratamento farmacológico , Nanopartículas Metálicas/química , Fotoquimioterapia , Telúrio/química , Animais , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Camundongos , Tamanho da Partícula , Processos Fotoquímicos , Espécies Reativas de Oxigênio/metabolismo , Propriedades de Superfície , Telúrio/farmacologiaRESUMO
Ag2S nanoparticles are increasingly important in biomedicine, such as in cancer imaging. However, there has been only limited success in the exploration of theranostic Ag2S nanoparticles for photoinduced cancer imaging and simultaneous therapy. Here we report size-dependent Ag2S nanodots (NDs) with well-defined nanostructure as a theranostic agent for multimodal imaging and simultaneous photothermal therapy. The NDs are precisely synthesized through carefully controlled growth of Ag2S in hollow human serum albumin nanocages. These NDs produce effective fluorescence in second near-infrared (NIR-II) region, distinct photoacoustic intensity, and good photothermal conversion in a size-dependent manner under light irradiation, thereby generating sufficient in vivo fluorescence and photoacoustic signals as well as potent hyperthermia at tumors. Moreover, Ag2S NDs possess ideal resistance to photobleaching, effective cellular uptake, preferable tumor accumulation, and in vivo elimination, thus facilitating NIR-II fluorescence/photoacoustics imaging with both ultrasensitivity and microscopic spatial resolution and simultaneous photothermal tumor ablation. These findings provide insight into the clinical potential of Ag2S nanodots for cancer theranostics.
Assuntos
Imagem Multimodal , Nanoestruturas/química , Imagem Óptica , Fototerapia , Pontos Quânticos/química , Compostos de Prata/química , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Humanos , Raios Infravermelhos , Camundongos , Neoplasias Experimentais/diagnóstico por imagem , Tamanho da Partícula , Processos Fotoquímicos , Porosidade , Albumina Sérica Humana/química , Compostos de Prata/síntese química , Compostos de Prata/farmacologia , Propriedades de SuperfícieRESUMO
Photodynamic therapy (PDT), as an emerging clinically approved modality, has been used for treatment of various cancer diseases. Conventional PDT strategies are mainly focused on superficial lesions because the wavelength of illumination light of most clinically approved photosensitizers (PSs) is located in the UV/VIS range that possesses limited tissue penetration ability, leading to ineffective therapeutic response for deep-seated tumors. The combination of PDT and nanotechnology is becoming a promising approach to fight against deep tumors. Here, the rapid development of new PDT modalities based on various smartly designed nanocomposites integrating with conventionally used PSs for deep tumor treatments is introduced. Until now many types of multifunctional nanoparticles have been studied, and according to the source of excitation energy they can be classified into three major groups: near infrared (NIR) light excited nanomaterials, X-ray excited scintillating/afterglow nanoparticles, and internal light emission excited nanocarriers. The in vitro and in vivo applications of these newly developed PDT modalities are further summarized here, which highlights their potential use as promising nano-agents for deep tumor therapy.
Assuntos
Nanocompostos/química , Neoplasias/tratamento farmacológico , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/uso terapêutico , Animais , Humanos , Espectroscopia de Luz Próxima ao Infravermelho , Raios XRESUMO
Multifunctional LaF3:Tb scintillating nanoparticles (ScNPs) coated with homogenous layers of silica and subsequently tethered with RB covalently were elaborated. The nanoconjugates with a high colloidal stability and biocompatibility could generate a reasonable amount of (1)O2 through efficient energy transfer upon external illumination, which enables them to be potentially applied in diagnosis and photodynamic therapy for deep seated tumour.
Assuntos
Elementos da Série dos Lantanídeos/química , Nanopartículas/química , Neoplasias Experimentais , Fotoquimioterapia , Dióxido de Silício/química , Tomografia Computadorizada por Raios X , Animais , Materiais Revestidos Biocompatíveis/química , Coloides/química , Terapia Combinada , Transferência de Energia , Camundongos , Neoplasias Experimentais/diagnóstico , Neoplasias Experimentais/tratamento farmacológico , Oxigênio/química , Raios XRESUMO
Photodynamic therapy (PDT) for deep-seated tumor is largely impeded by the limited penetration depth of excitation light in tissue. X-ray is considered as an ideal energy source to activate photosensitizers (PSs) located deep within the body with the assistance of scintillating nanoparticles (ScNPs). However, the efficacy under this concept is not satisfying due to the low scintillating luminescence and weak energy transfer from ScNPs to PSs. Here, mesoporous LaF3:Tb ScNPs were successfully synthesized by a facile hydrothermal process to act as PS carriers and X-ray energy transducers, owing to their good ionizing radiation stopping power and high luminescence efficiency. The formation mechanism of porous structure was elucidated in detail with classical crystallization theory. After a systematic investigation, LaF3:Tb ScNPs with optimized scintillating luminescence were obtained for loading Rose Bengal (RB) to establish an efficient FRET system, owing to their excellent spectral match. The FRET efficiency between ScNPs and RB was calculated to be as high as 85%. Under irradiation, enhanced (1)O2 generation induced by LaF3:Tb-RB nanocomposites via FRET process was detected. This LaF3:Tb-RB FRET system shows great potential to be applied in X-ray stimulated PDT for deep-seated tumors in the future.