RESUMEN
Mitochondrial RNA (mtRNA) plays a critical role in synthesis of mitochondrial proteins. Interfering mtRNA is a highly effective way to induce cell apoptosis. Herein, we report a near-infrared (NIR) light-mediated mitochondrial RNA modification approach for long-term imaging and effective suppression of tumors. A tumor-targetable NIR fluorescent probe f-CRI consisting of a cyclic RGD peptide, a NIR fluorophore IR780, and a singlet oxygen (1 O2 )-labile furan group for RNA modification was rationally designed and synthesized. This probe was demonstrated to dominantly accumulate in cellular mitochondria and could be covalently conjugated onto mtRNA upon 808â nm irradiation resulting in prolonged retention in tumors. More notably, this covalent modification of mtRNA by f-CRI could perturb the function of mitochondria leading to remarkable tumor suppression. We thus envision that our current approach would offer a potential approach for cancer RNA interference therapeutics.
Asunto(s)
Neoplasias , Fotoquimioterapia , Humanos , ARN Mitocondrial/metabolismo , ARN Mitocondrial/uso terapéutico , Interferencia de ARN , Neoplasias/tratamiento farmacológico , Fotoquimioterapia/métodos , Mitocondrias/metabolismo , Colorantes Fluorescentes/metabolismoRESUMEN
Accurately assessing the radiation level of tumors and surrounding tissues is of great significance for the optimization of clinical therapeutic interventions as well as minimizing the radiation-induced side effects. Therefore, the development of noninvasive and sensitive biological dosimeters is vital to achieve quantitative detection of a radiation dose in a living system. Herein, as a proof of concept, we report a tumor-targeted and caspase-3-activatable NIR fluorogenic probe AcDEVD-Cy-RGD consisting of a hemicyanine fluorophore as a signal reporter, a caspase-3 specific Asp-Glu-Val-Asp (DEVD) peptide, and a cyclic Arg-Gly-Asp peptide (cRGD) for tumor targeting. Upon cleavage with activated caspase-3, this probe not only displays the lighted-up NIR fluorescence, but also ratiometric photoacoustic (PA710/PA680) signals concurrently in a caspase-3 concentration-dependent manner, allowing for sensitive and quantitative detection of caspase-3 activity through both fluorescence and PA imaging, which provides the possibility for real-time monitoring of tumor cell apoptosis in a living system. More notably, we utilized this probe to successfully realize the direct visualization of tumor response to chemo- or radiotherapy and, for the first time, achieve the accurate estimation of radiation doses imparted to the tumors. We thus believe that our current strategy would offer an attractive and valuable means for the precise assessment of locally delivered radiation doses in various clinical settings.
Asunto(s)
Neoplasias , Técnicas Fotoacústicas , Apoptosis/efectos de la radiación , Caspasa 3 , Relación Dosis-Respuesta en la Radiación , Humanos , Neoplasias/diagnóstico por imagen , Neoplasias/radioterapia , Imagen ÓpticaRESUMEN
Developing an accurate and reliable detection technique for early embryonic apoptosis is of great significance for real-time monitoring and evaluation of embryonic development in living systems. Herein, we have rationally designed and synthesized a novel near-infrared (NIR) fluorogenic probe CGK(QSY21)DEVD-Cy5.5 for real-time imaging of embryonic apoptosis. This probe is constructed with a NIR dye Cy5.5, a fluorescence quencher QSY21, and a peptide substrate Asp-Glu-Val-Asp (DEVD) of the caspase-3 enzyme that is a key executor of cell apoptosis. The probe was initially nonfluorescent in aqueous solution but emitted strong NIR fluorescence upon specific cleavage by activated caspase-3 in a concentration-dependent manner. Taking advantage of this unique feature, this fluorogenic probe was for the first time used for real-time imaging of caspase-3 activity in apoptotic embryos. More notably, significant fluorescence enhancement was solely determined from the apoptotic embryos with the treatment of the probe both in vitro and in vivo, highly suggesting that this probe has great potential to monitor the apoptosis of embryos. We thus envision that this probe would provide a very useful means for real-time visualization and accurate evaluation of embryonic development in the future.
Asunto(s)
Apoptosis , Colorantes Fluorescentes , Caspasa 3 , Desarrollo Embrionario , Fluorescencia , PéptidosRESUMEN
Developing endogenous photo-activated theranostic platforms to overcome the limitation of low tissue-penetration from external light sources is highly significant for cancer diagnosis and treatment. We report a H2 O2 -initiated chemiluminescence (CL)-triggered nanoparticle aggregation strategy to activate theranostic functions of gold nanoparticles (AuNPs) for effective tumor imaging and therapy. Two types of AuNPs (tAuNP & mAuNP) were designed and fabricated by conjugating 2,5-diphenyltetrazole and methacrylic acid onto the surface of AuNPs, respectively. Luminol was adsorbed onto the mAuNPs to afford self-illuminating mAuNP/Lu NPs that could produce strong CL by reaction with H2 O2 in the tumor microenvironment, which triggers significant aggregation of AuNPs resulting in enhanced accumulation and retention of AuNPs for activated photoacoustic imaging and photothermal therapy of tumors. We thus believe that this approach may offer a promising tool for effective tumor treatment.
Asunto(s)
Antineoplásicos/uso terapéutico , Oro/química , Peróxido de Hidrógeno/química , Nanopartículas del Metal/química , Neoplasias , Nanomedicina Teranóstica , Humanos , Luminiscencia , Neoplasias/diagnóstico por imagen , Neoplasias/tratamiento farmacológico , Microambiente TumoralRESUMEN
Improving the enrichment of drugs or theranostic agents within tumors is very vital to achieve effective cancer diagnosis and therapy while greatly reducing the dosage and damage to normal tissues. Herein, as a proof of concept, we for the first time report a red light-initiated probe-RNA cross-linking (RLIPRC) strategy that can not only robustly promote the accumulation and retention of the probe in the tumor for prolonged imaging but also significantly inhibits the tumor growth. A near-infrared (NIR) fluorescent probe f-CR consisting of a NIR dye (Cyanine 7) as a signal reporter, a cyclic-(arginine-glycine-aspartic acid) (cRGD) peptide for tumor targeting, and a singlet oxygen (1O2)-sensitive furan moiety for RNA cross-linking was rationally designed and synthesized. This probe possessed both passive and active tumor targeting abilities and emitted intense NIR/photoacoustic (PA) signals, allowing for specific and sensitive dual-modality imaging of tumors in vivo. Notably, probe f-CR could be specifically and covalently cross-linked to cytoplasmic RNAs via the cycloaddition reaction between furan and adenine, cytosine, or guanine under the oxidation of 1O2 generated in situ by irradiation of methylene blue (MB) with 660 nm laser light, which effectively blocks the exocytosis of the probes resulting in enhanced tumor accumulation and retention. More excitingly, for the first time, we revealed that the covalent cross-linking of probe f-CR to cytoplasmic RNAs could induce severe apoptosis of cancer cells leading to remarkable tumor suppression. This study thus represents the first red light-initiated RNA cross-linking system with high potential to improve the diagnostic and therapeutic outcomes of tumors in vivo.
Asunto(s)
Citoplasma/metabolismo , Rayos Infrarrojos , Imagen Molecular/métodos , Fotoquimioterapia/métodos , ARN/metabolismo , Carbocianinas/química , Línea Celular Tumoral , Citoplasma/efectos de la radiación , Humanos , Oxígeno Singlete/química , Oxígeno Singlete/metabolismoRESUMEN
Mitochondria plays pivotal roles in energy production and apoptotic pathways. Mitochondria-targeting strategy has been recognized as a promising way for cancer theranostics. Thus, spatiotemporally manipulating the prolonged retention of theranostic agents within mitochondria is considerably significant in cancer diagnosis and therapy. Herein, as a proof-of concept, we for the first time report a sulfenic acid-responsive platform on controlled immobilization of probes within mitochondria for prolonged tumor imaging. A novel near-infrared (NIR) probe DATC constructed with a NIR dye (Cy5) as signal unit, a cationic triphenylphosphonium (TPP) for mitochondria targeting, and a sulfenic acid-reactive group (1,3-cyclohexanedione) for mitochondrial fixation was rationally designed and synthesized. This probe displayed good target ability to mitochondria and could act as a promising fluorescent probe for specific visualization of endogenous protein sulfenic acids expressed in the mitochondria. Moreover, the probe could be spontaneously fixed on site through the specific reaction and covalent binding to the sulfenic acids of oxidized proteins under oxidative stress, resulting in enhanced intracellular uptake and prolonged retention. We thus believe that this mitochondria-targeted and locational immobilization strategy may offer a new insight for long-term tumor imaging and effective therapy.
Asunto(s)
Neoplasias de la Mama/diagnóstico por imagen , Carbocianinas/química , Colorantes Fluorescentes/química , Mitocondrias/química , Ácidos Sulfénicos/química , Células 3T3 , Animales , Carbocianinas/metabolismo , Carbocianinas/farmacología , Línea Celular Tumoral , Femenino , Colorantes Fluorescentes/metabolismo , Colorantes Fluorescentes/farmacología , Rayos Infrarrojos , Ratones , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Estructura Molecular , Imagen Óptica , Ácidos Sulfénicos/metabolismoRESUMEN
Tumor microenvironment plays a pivotal role in the growth and metastasis of tumors, and has become a promising target for precise diagnosis and treatment of tumors. Herein, a novel smart NIR theranostic probe Cy-1 that can simultaneously respond to low intracellular pH and reductive glutathione (GSH) is reported. This probe has demonstrated to be able to intermolecularly undergo a biologically compatible CBT-Cys condensation reaction to selectively form large nanoaggregates in the tumor microenvironment resulting in its enhanced accumulation and retention in the tumor, which as a consequence significantly improves the sensitivity of NIR/photoacoustic imaging and photothermal therapeutic efficacy of tumors in living mice. We thus believe that this dual stimuli-mediated self-assembly strategy may offer a promising and universal platform for cancer theranostics.
Asunto(s)
Diagnóstico por Imagen/métodos , Rayos Infrarrojos , Sondas Moleculares/metabolismo , Terapia Fototérmica/métodos , Animales , Línea Celular Tumoral , Glutatión/metabolismo , Humanos , Concentración de Iones de Hidrógeno , Ratones , Sondas Moleculares/química , Técnicas Fotoacústicas , Microambiente TumoralRESUMEN
Developing activatable near-infrared (NIR) probes to specifically monitor and visualize the activities of cancer-related enzymes is highly significant yet challenging in early cancer diagnosis. Taking advantage of the unique photophysical characteristics of aggregation-induced emission (AIE) fluorophores, here we design and synthesize a novel activatable probe QMTP by conjugating an AIE fluorophore quinolone-malononitrile to a hydrophilic phosphate-modified phenol group. The probe was initially non-fluorescent in aqueous solution due to its good water solubility, but was readily activated to generate a strong NIR fluorescence upon treatment with alkaline phosphatase (ALP), which enables specific detection of ALP activity. Furthermore, we have employed QMTP to monitor and spatially map the activity of endogenous ALP both in cancer cells and in drug-treated zebrafish larvae. The experimental results reveal that the QMTP probe has great specificity and sensitivity for ALP detection. We thus believe that our work offers a promising tool for accurate detection of ALP-associated diseases in preclinical applications.
Asunto(s)
Fosfatasa Alcalina/química , Fosfatasa Alcalina/metabolismo , Colorantes Fluorescentes/química , Rayos Infrarrojos , Límite de Detección , Células 3T3 , Animales , Citometría de Flujo , Células HeLa , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Larva/enzimología , Ratones , Nitrilos/química , Imagen Óptica , Quinolonas/química , Pez CebraRESUMEN
Mitochondria as one of the key subcellular organelles have been well recognized as a promising druggable target and are closely associated with energy supply and various cellular functions. Realizing high accumulation and prolonged retention of radiosensitizers in the cellular mitochondria of tumors is an effective way to improve radiotherapeutic efficacy. Herein, we develop mitochondria-targeting and protein sulfenic acid (PSA)-reactive gold nanoparticles (dAuNP-TPP) that are fabricated by incorporating triphenylphosphine and 1,3-cyclohexanedione onto the surface of AuNPs (â¼20 nm) to improve CT imaging and radiotherapeutic efficacy of tumors. Taking advantage of the specific mitochondrial targeting and PSA-mediated on-site covalent immobilization, this nanosystem shows significantly enhanced accumulation and retention in mitochondria with approximately 5.22-fold higher enrichment than nonimmobilizable AuNP-TPP. More notably, the covalent immobilization of dAuNP-TPP in cellular mitochondria could induce a dramatic reduction of ATP, leading to serious mitochondrial disruption, combined with the radiosensitization effect, in consequence achieving efficient radiotherapy of breast tumors in vivo. This subcellular organelle-targeted and immobilizable strategy may offer a valuable and universal tool for efficient tumor treatment.
Asunto(s)
Nanopartículas del Metal , Nanopartículas , Neoplasias , Línea Celular Tumoral , Oro , Humanos , Mitocondrias/metabolismo , Neoplasias/tratamiento farmacológico , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Hydrogen sulfide (H2S) as an important biological gasotransmitter plays a pivotal role in many physiological and pathological processes. The sensitive and quantitative detection of H2S level is therefore crucial for precise diagnosis and prognosis evaluation of various diseases but remains a huge challenge due to the lack of accurate and reliable analytical methods in vivo. In this work, we report a smart, H2S-responsive and depleting nanoplatform (ZNNPs) for quantitative and real-time imaging of endogenous H2S for early diagnosis and treatment of H2S-associated diseases. We show that ZNNPs exhibit unexpected NIR conversion (F1070 â F720) and ratiometric photoacoustic (PA680/PA900) signal responsiveness towards H2S, allowing for sensitive and quantitative visualization of H2S in acute hepatotoxicity, cerebral hemorrhage model as well as colorectal tumors in living mice. ZNNPs@FA simultaneously scavenges the mitochondrial H2S in tumors leading to significant ATP reduction and severe mitochondrial damage, together with the activated photodynamic effect, resulting in efficient suppression of colorectal tumor growth in mice. We believe that this platform may provide a powerful tool for studying the vital impacts of H2S in related diseases.
Asunto(s)
Sulfuro de Hidrógeno , Neoplasias , Fotoquimioterapia , Animales , Ratones , Neoplasias/diagnóstico por imagen , Neoplasias/tratamiento farmacológicoRESUMEN
Accurate diagnosis and efficient treatment of tumors are highly significant in battling cancer. Near-infrared II (NIR-II) fluorescence imaging shows big promise for deep tumor visualization in living systems due to high temporal and spatial resolution and deep tissue penetration capability, whereas the development of efficient NIR-II probes for tumor theranostics still faces a huge challenge. Herein, we have designed and constructed intelligent mPEG5000-PCL3000-encapsulated NIR-II nanoprobe ZM1068-NPs that showed great chemical stability and excellent biocompatibility. With the merits of the strong fluorescence in the NIR-II region and prominent optical-thermal conversion efficiency, this probe was successfully used for NIR-II imaging-guided surgery and photothermal therapy of breast carcinoma in living mice. More notably, it was for the first time found that ZM1068 dyes could be covalently on-site-immobilized within tumors through the thiol-chlor nucleophilic substitution reaction, resulting in improved tumor accumulation and retention time. We thus envision that this probe may provide an attractive means for precise cancer diagnosis and treatment.
Asunto(s)
Colorantes Fluorescentes/química , Nanopartículas/química , Neoplasias/diagnóstico por imagen , Neoplasias/cirugía , Polietilenglicoles/química , Animales , Línea Celular Tumoral , Colorantes Fluorescentes/uso terapéutico , Rayos Infrarrojos , Ratones , Nanopartículas/uso terapéutico , Imagen Óptica , Terapia Fototérmica , Polietilenglicoles/uso terapéutico , Cirugía Asistida por Computador , Nanomedicina TeranósticaRESUMEN
Developing intelligent and morphology-transformable nanomaterials that can spatiotemporally undergo stimulus-responsive size transformation holds great promise for improving the tumor delivery efficiency of drugs in vivo. Here, we report a smart size-transformable theranostic probe Ce6-Leu consisting of a leucine amino peptidase (LAP) and glutathione (GSH) dual-responsive moiety, an 1,2-aminothiol group, and a clinically used photosensitizer Ce6. This probe tends to self-assemble into uniform nanoparticles with an initial size of â¼80 nm in aqueous solution owing to the amphiphilic feature. Surprisingly, taking advantage of the biocompatible CBT-Cys condensation reaction, the large nanoprobes can be transformed into tiny nanoparticles (â¼23 nm) under the joint action of LAP and GSH in a tumor microenvironment, endowing them with great tumor accumulation and deep tissue penetration. Concomitantly, this LAP/GSH-driven disassembly and size shrinkage of Ce6-Leu can also activate the fluorescence/magnetic resonance signals and the photodynamic effect for enhanced multimodal imaging-guided photodynamic therapy of human liver HepG2 tumors in vivo. More excitingly, the Mn2+-chelating probe (Ce6-Leu@Mn2+) was demonstrated to have the capability to catalyze endogenous H2O2 to persistently release O2 at the hypoxic tumor site, as a consequence improving the oxygen supply to boost the radiotherapy effect. We thus believe that this LAP/GSH-driven size-transformable nanosystem would offer a novel advanced technology to improve the drug delivery efficiency for achieving precise tumor diagnosis and treatment.
Asunto(s)
Antineoplásicos/farmacología , Materiales Biocompatibles/farmacología , Glutatión/metabolismo , Leucil Aminopeptidasa/metabolismo , Fotoquimioterapia , Fármacos Fotosensibilizantes/farmacología , Nanomedicina Teranóstica , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Materiales Biocompatibles/síntesis química , Materiales Biocompatibles/química , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Clorofilidas/química , Clorofilidas/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Células Hep G2 , Humanos , Neoplasias Hepáticas Experimentales/tratamiento farmacológico , Neoplasias Hepáticas Experimentales/metabolismo , Neoplasias Hepáticas Experimentales/patología , Ensayo de Materiales , Estructura Molecular , Imagen Óptica , Tamaño de la Partícula , Fármacos Fotosensibilizantes/químicaRESUMEN
Radiotherapy (RT) has become one of the most widely used treatments for malignant tumors in clinics. Developing a novel radiosensitizer for the integration of precise diagnosis and effective radiotherapy against hypoxic tumors is desirable but remains a great challenge. Herein, protein sulfenic acid reactive gold nanoparticles as effective radiosensitizers were for the first time reported for enhanced X-ray computed tomography (CT) imaging and radiotherapy of tumors in vivo. The gold nanoparticles were decorated with biocompatible poly(ethylene glycol), folic acid (FA), and sulfenic acid reactive groups 1,3-cyclohexanedione (CHD). Such a nanostructure enables on-site immobilization within tumors under oxidative stress through the specific reaction between CHD and endogenous protein sulfenic acids resulting in enhanced accumulation and retention of gold nanoparticles within tumors, which remarkably improves the sensitivity of CT imaging and the radiotherapeutic efficacy of tumors in living mice. This study thus is the first to demonstrate that protein sulfenic acid reactive gold nanoparticles with a tumor anchoring function may serve as effective radiosensitizers for clinical X-ray theranostic application in the future.
Asunto(s)
Nanopartículas del Metal , Neoplasias , Animales , Línea Celular Tumoral , Oro , Ratones , Neoplasias/diagnóstico por imagen , Neoplasias/tratamiento farmacológico , Neoplasias/radioterapia , Ácidos Sulfénicos , Tomografía Computarizada por Rayos XRESUMEN
Developing novel small-molecule-based probes with both deep tissue imaging and therapeutic functions is highly significant in cancer diagnosis and treatment. Herein, we report a novel second near-infrared (NIR-II) fluorescent probe QT-RGD constructed with a NIR-II emissive organic fluorophore and two cyclic-(arginine-glycine-aspartic acid) (cRGD) peptides that can specifically bind to the tumor-associated αvß3 integrin for accurate tumor diagnosis and targeting therapy. The isotopic 125I-labeled probe exhibited great tumor targeting ability and emitted intensive NIR-II/photoacoustic (PA)/single-photon emission computed tomography (SPECT) signals, which allows specific and sensitive multimodal visualization of tumors in vivo. More notably, this probe could also be applied for effective imaging-guided photothermal therapy (PTT) of tumors in mouse models owing to its prominent photothermal conversion efficiency and excellent photothermal stability. We thus envision that our work which unveils a combination of NIR-II/PA/SPECT imaging and PTT would offer a valuable means of improving tumor diagnostic accuracy as well as therapeutic efficacy.
Asunto(s)
Integrina alfaVbeta3/antagonistas & inhibidores , Nanopartículas , Proteínas de Neoplasias/antagonistas & inhibidores , Neoplasias Experimentales , Imagen Óptica , Terapia Fototérmica , Tomografía Computarizada por Tomografía Computarizada de Emisión de Fotón Único , Nanomedicina Teranóstica , Animales , Femenino , Colorantes Fluorescentes/química , Colorantes Fluorescentes/farmacología , Ratones , Nanopartículas/química , Nanopartículas/uso terapéutico , Proteínas de Neoplasias/metabolismo , Neoplasias Experimentales/diagnóstico por imagen , Neoplasias Experimentales/terapia , Péptidos Cíclicos/química , Péptidos Cíclicos/farmacologíaRESUMEN
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.