RESUMO
RNA interference (RNAi) has proved to be a promising modality for disease treatment. However, the promise of conventional RNA therapeutics for clinical application is severely impeded by low delivery efficiency and susceptibility of RNAs to serum RNases. Therefore, developing advanced RNAi technology is an increasing demand for achieving precise medicine. Herein, for the first time, we propose an alkaline phosphatase (ALP)-controllable and red light-activated RNA modification (ALARM) approach for anti-tumor therapeutic application. An ALP-responsive NIR fluorogenic probe f-RCP consisting of a tumor-targeting cyclic RGD peptide, an ALP-activated photosensitizer CyOP, and an 1O2-susceptible furan module for RNA modification was rationally designed and synthesized. Studies have demonstrated that f-RCP can specifically target to liver carcinoma HepG2 cells and spontaneously emit activated NIR/photoacoustic signals upon cleavage by the ALP enzyme, allowing for sensitive detection of ALP-positive tumors. More notably, we surprisingly found that the capability of f-RCP producing singlet oxygen (1O2) under red light irradiation could be simultaneously unlocked, which can ignite the covalent cyclization reaction between furan and nucleobases of intracellular RNA molecules, leading to significant mitochondrial damage and severe apoptosis of tumor cells, in consequence realizing efficient tumor suppression. Most importantly, the potential therapeutic mechanism was first explored on the transcriptomic level. This delicate ALARM strategy may open up new insights into cancer gene therapy.
Assuntos
Fosfatase Alcalina , Neoplasias , Humanos , Luz , Corantes Fluorescentes/química , RNARESUMO
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.
Assuntos
Neoplasias , Técnicas Fotoacústicas , Apoptose/efeitos da radiação , Caspase 3 , Relação Dose-Resposta à Radiação , Humanos , Neoplasias/diagnóstico por imagem , Neoplasias/radioterapia , Imagem ÓpticaRESUMO
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.
Assuntos
Apoptose , Corantes Fluorescentes , Caspase 3 , Desenvolvimento Embrionário , Fluorescência , PeptídeosRESUMO
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.
Assuntos
Antineoplásicos/uso terapêutico , Ouro/química , Peróxido de Hidrogênio/química , Nanopartículas Metálicas/química , Neoplasias , Nanomedicina Teranóstica , Humanos , Luminescência , Neoplasias/diagnóstico por imagem , Neoplasias/tratamento farmacológico , Microambiente TumoralRESUMO
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.
Assuntos
Citoplasma/metabolismo , Raios Infravermelhos , Imagem Molecular/métodos , Fotoquimioterapia/métodos , RNA/metabolismo , Carbocianinas/química , Linhagem Celular Tumoral , Citoplasma/efeitos da radiação , Humanos , Oxigênio Singlete/química , Oxigênio Singlete/metabolismoRESUMO
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.
Assuntos
Diagnóstico por Imagem/métodos , Raios Infravermelhos , Sondas Moleculares/metabolismo , Terapia Fototérmica/métodos , Animais , Linhagem Celular Tumoral , Glutationa/metabolismo , Humanos , Concentração de Íons de Hidrogênio , Camundongos , Sondas Moleculares/química , Técnicas Fotoacústicas , Microambiente TumoralRESUMO
Gold nanoparticles have been widely used in engineering, material chemistry, and biomedical applications owing to their ease of synthesis and functionalization, localized surface plasmon resonance (LSPR), great chemical stability, excellent biocompatibility, tunable optical and electronic property. In recent years, the decoration and modification of gold nanoparticles with small molecules, ligands, surfactants, peptides, DNA/RNA, and proteins have been systematically studied. In this review, we summarize the recent approaches on stimuli-triggered self-assembly of gold nanoparticles and introduce the breakthrough of gold nanoparticles in disease diagnosis and treatment. Finally, we discuss the current challenge and future prospective of stimuli-responsive gold nanoparticles for biomedical applications.
Assuntos
Nanopartículas Metálicas , Ouro/química , Nanopartículas Metálicas/química , Peptídeos , Proteínas , Ressonância de Plasmônio de Superfície , DNA/química , RNA/químicaRESUMO
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.
Assuntos
Nanopartículas Metálicas , Nanopartículas , Neoplasias , Linhagem Celular Tumoral , Ouro , Humanos , Mitocôndrias/metabolismo , Neoplasias/tratamento farmacológico , Espécies Reativas de Oxigênio/metabolismoRESUMO
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.
Assuntos
Sulfeto de Hidrogênio , Neoplasias , Fotoquimioterapia , Animais , Camundongos , Neoplasias/diagnóstico por imagem , Neoplasias/tratamento farmacológicoRESUMO
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.
Assuntos
Corantes Fluorescentes/química , Nanopartículas/química , Neoplasias/diagnóstico por imagem , Neoplasias/cirurgia , Polietilenoglicóis/química , Animais , Linhagem Celular Tumoral , Corantes Fluorescentes/uso terapêutico , Raios Infravermelhos , Camundongos , Nanopartículas/uso terapêutico , Imagem Óptica , Terapia Fototérmica , Polietilenoglicóis/uso terapêutico , Cirurgia Assistida por Computador , Nanomedicina TeranósticaRESUMO
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.