RESUMO
Although gastric cancer (GC) is one of the most frequent malignant tumors in the digestive tract with high morbidity and mortality, it remains a diagnostic dilemma due to its reliance on invasive biopsy or insensitive assays. Herein, we report a fluorescent gastric cancer reporter (FGCR) with activatable near-infrared fluorescence (NIRF) signals and high renal-clearance efficiency for the detection of orthotopic GC in a murine model via real-time imaging and remote urinalysis. In the presence of gastric-tumor-associated ß-galactosidase (ß-Gal), FGCR can be fluorescently activated for in vivo NIRF imaging. Relying on its high renal-clearance efficiency (â¼95% ID), it can be rapidly excreted through kidneys to urine for the ultrasensitive detection of tumors with a diameter down to â¼2.1 mm and for assessing the prognosis of oxaliplatin-based chemotherapy. This study not only provides a new approach for noninvasive auxiliary diagnosis and prognosis of GC but also provides guidelines for the development of fluorescence probes for cancer diagnosis.
Assuntos
Corantes Fluorescentes , Imagem Óptica , Neoplasias Gástricas , beta-Galactosidase , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/urina , Neoplasias Gástricas/patologia , Animais , beta-Galactosidase/metabolismo , Corantes Fluorescentes/química , Humanos , Camundongos , Linhagem Celular Tumoral , Camundongos NusRESUMO
BACKGROUND: Although it is thought that prostatitis or benign prostatic hyperplasia (BPH) is related to prostate cancer (PCa), the underlying causal effects of these diseases are unclear. METHODS: We assessed the causal relationship between prostatitis or BPH and PCa using a two-sample Mendelian randomization (MR) approach. The data utilized in this study were sourced from genome-wide association study. The association of genetic variants from cohorts of prostatitis or BPH and PCa patients was determined using inverse-variance weighted and MR Egger regression techniques. The direction of chance was determined using independent genetic variants with genome-wide significance (P < 5 × 10-6). The accuracy of the results was confirmed using sensitivity analyses. RESULTS: MR analysis showed that BPH had a significant causal effect on PCa (Odds Ratio = 1.209, 95% Confidence Interval: 0.098-0.281, P = 5.079 × 10- 5) while prostatitis had no significant causal effect on PCa (P > 0.05). Additionally, the pleiotropic test and leave-one-out analysis showed the two-sample MR analyses were valid and reliable. CONCLUSIONS: This MR study supports that BPH has a positive causal effect on PCa, while genetically predicted prostatitis has no causal effect on PCa. Nonetheless, further studies should explore the underlying biochemical mechanism and potential therapeutic targets for the prevention of these diseases.
Assuntos
Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Hiperplasia Prostática , Neoplasias da Próstata , Prostatite , Humanos , Masculino , Neoplasias da Próstata/genética , Hiperplasia Prostática/genética , Prostatite/genética , Prostatite/complicações , Polimorfismo de Nucleotídeo Único , Predisposição Genética para DoençaRESUMO
Optical nanoparticles are promising diagnostic tools; however, their shallow optical imaging depth and slow clearance from the body have impeded their use for in vivo disease detection. To address these limitations, we develop activatable polyfluorophore nanosensors with biomarker-triggered nanoparticle-to-molecule pharmacokinetic conversion and near-infrared fluorogenic turn-on response. Activatable polyfluorophore nanosensors can accumulate at the disease site and react with disease-associated proteases to undergo in situ enzyme-catalysed depolymerization. This disease-specific interaction liberates renal-clearable fluorogenic fragments from activatable polyfluorophore nanosensors for non-invasive longitudinal urinalysis and outperforms the gold standard blood and urine assays, providing a level of sensitivity and specificity comparable to those of invasive biopsy and flow cytometry analysis. In rodent models, activatable polyfluorophore nanosensors enable ultrasensitive detection of tumours (1.6 mm diameter) and early diagnosis of acute liver allograft rejection. We anticipate that our modular nanosensor platform may be applied for early diagnosis of a range of diseases via a simple urine test.
Assuntos
Nanopartículas , Neoplasias , Aloenxertos , Detecção Precoce de Câncer , Humanos , RimRESUMO
Immunotherapy has provided a promising modality for cancer treatment, while it often has the issues of limited response rates and potential off-target side effects in clinical practice. We herein report the construction of semiconducting polymer pro-nanomodulators (SPpMs) with ultrasound (US)-mediated activatable pharmacological actions for deep-tissue sono-immunotherapy of orthotopic pancreatic cancer. Such SPpMs consist of a sonodynamic semiconducting polymer backbone grafted with poly(ethylene glycol) chains linked with two immunomodulators (a programmed death-ligand 1 blocker and an indoleamine 2,3-dioxygenase inhibitor) via a singlet oxygen (1 O2 )-cleavable segment. In view of the excellent sonodynamic property of the semiconducting polymer core, SPpMs enable effective generation of 1 O2 under US treatment, even in a deep-tissue depth up to 12â cm. The generated 1 O2 not only ablates tumors via a sonodynamic effect and induces immunogenic cell death, but also destroys the 1 O2 -cleavable segments to allow in situ release of immunomodulators in tumors. This synergetic action results in boosted antitumor immune response via reversing two tumor immunosuppressive pathways. As such, SPpMs mediate deep-tissue sono-immunotherapy to completely eradicate orthotopic pancreatic cancer and effectively prevent tumor metastasis. Moreover, such an immune activation reduces the possibility of immune-related adverse events. This study thus provides a smart activatable nanoplatform for precise immunotherapy of deep-seated tumors.
Assuntos
Nanopartículas , Neoplasias , Neoplasias Pancreáticas , Humanos , Polímeros , Neoplasias/terapia , Neoplasias Pancreáticas/diagnóstico por imagem , Neoplasias Pancreáticas/tratamento farmacológico , Polietilenoglicóis , Imunoterapia , Linhagem Celular Tumoral , Neoplasias PancreáticasRESUMO
Fluorescent probes are attractive in diagnosis and sensing. However, most reported fluorophores can only detect one or few analytes/parameters, notably limiting their applications. Here we have designed three phenanthridine-based fluorophores (i.e., B1, F1, and T1 with 1D, 2D, and 3D molecular configuration, respectively) capable of monitoring various microenvironments. In rigidifying media, all fluorophores show bathochromic emissions but with different wavelength and intensity changes. Under compression, F1 shows a bathochromic emission of over 163â nm, which results in organic fluorophore-based full-color piezochromism. Moreover, both B1 and F1 exhibit an aggregation-caused quenching (ACQ) behavior, while T1 is an aggregation-induced emission (AIE) fluorophore. Further, F1 and T1 selectively concentrate in cell nucleus, whereas B1 mainly stains the cytoplasm in live cell imaging. This work provides a general design strategy of versatile fluorophores for microenvironmental monitoring.
Assuntos
Diagnóstico por Imagem , Corantes Fluorescentes , Núcleo Celular , CitoplasmaRESUMO
Drug-induced renal failure (DIRF) poses a serious medical complication with high mortality risk. However, early diagnosis or prognosis of DIRF remain challenging, as current methods rely on detecting late-stage biomarkers. Herein we present a library of zwitterionic unimolecular hemicyanines (ZCs) available for constructing activatable reporters to detect DIRF since its initial stage. Zwitterionic properties of these probes are achieved through interspersedly integrating alkyl sulfonates and quaternary ammonium cations onto hemicyanine skeleton, which result in record low plasma protein binding (<5 %) and remarkable renal clearance efficiencies (≈96 %). An activatable reporter ZCRR is further developed by masking the optimal candidate ZC6 with a tetrapeptide specifically cleavable by caspase-8, an initiating indicator of apoptosis. In living mice with cisplatin-induced DIRF, systematically administered ZCRR efficiently accumulates in kidneys and responds to elevated caspase-8 for near-infrared fluorescence signals 'turn-on', enabling sensitive detection of intrarenal apoptosis 60â h earlier than clinical methods, and precise evaluation of apoptosis remediation effects by different medications on DIRF mice. As it's urinary excretable, ZCRR also allows for remote detection of DIRF and predicting renoprotective efficacy through in vitro optical urinalysis. This study thus presents unimolecular renal clearable scaffolds that are applicable to developing versatile activatable reporters for renal diseases management.
Assuntos
Injúria Renal Aguda , Corantes Fluorescentes , Camundongos , Animais , Corantes Fluorescentes/química , Caspase 8/metabolismo , Prognóstico , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/diagnóstico , Diagnóstico PrecoceRESUMO
Chemiluminescence imaging has been recognized as a valuable tool for ultrasensitive detection of physio-pathological events through elimination of background autofluorescence. However, most chemiluminescent nanoprobes suffer from shallow imaging depths and slow clearance from living bodies, which impede their use in clinical settings. We herein report size-transformable nanoreporters (ADN1 and ADN2) that could be activated at disease site by superoxide anion (O2 â - ) to trigger nanostructure disassembly into renal excretable fluorescent fragments as well as chemiluminescence turn-on for crosstalk-free duplex chemo-fluorescence imaging and in vitro urinalysis. In peritonitis mouse model, we demonstrate that the representative nanoreporter ADN1 spontaneously accumulates at the disrupted peritoneum and is cleaved by upregulated O2 â - to initiate depolymerization and result in red chemiluminescence at 620â nm, enabling sensitive detection of peritonitis at least 19â h earlier than gold standard histological assays. Additionally, the incorporation of a near-infrared (NIR) dye into ADN1 results in ADN2 exhibiting intense and red-shifted chemiluminescence at ≈800â nm, which permits early detection of deeply seated diseases such as drug-induced hepatotoxicity. This study thus showcases a modular design strategy that is not only applicable to developing versatile chemiluminescent nanoprobes with switchable pharmacokinetics for early disease diagnosis, but also promising for future clinical translations.
Assuntos
Luminescência , Superóxidos , Animais , Camundongos , Corantes Fluorescentes/química , Imagem Óptica/métodos , RimRESUMO
Activatable phototheranostics holds promise for precision cancer treatment owing to the "turn-on" signals and therapeutic effects. However, most activatable phototheranostic probes only possess photodynamic therapy (PDT) or photothermal therapy (PTT), which suffer from poor therapeutic efficacy due to deficient cellular oxygen and complex tumor microenvironment. We herein report a dual-locked activatable phototheranostic probe that activates near-infrared fluorescence (NIRF) signals in tumor, triggers PDT in response to a tumor-periphery biomarker, and switches from PDT to PTT upon detecting a tumor-core-hypoxia biomarker. This PDT-PTT auto-regulated probe exhibits complete tumor ablation under the photoirradiation of a single laser source by producing cytotoxic singlet oxygen at the tumor periphery and generating hyperthermia at tumor-core where is too hypoxic for PDT. This dual-locked probe represents a promising molecular design approach toward precise cancer phototheranostics.
Assuntos
Neoplasias , Fotoquimioterapia , Biomarcadores , Linhagem Celular Tumoral , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/terapia , Terapia Fototérmica , Nanomedicina Teranóstica , Microambiente TumoralRESUMO
OBJECTIVE: We investigated the clinical value of the Controlling Nutritional Status score in evaluating the prognosis of patients with non-muscle invasive bladder cancer. METHODS: We conducted a retrospective analysis of the clinical data of 88 patients with non-muscle invasive bladder cancer who underwent transurethral resection of bladder tumor or partial cystectomy between January 2011 and May 2015 in a single center. The patients were divided into groups base on high (>1) and low (≤1) Controlling Nutritional Status score. RESULTS: Clinical and demographic data of the patient groups were analyzed using the Kaplan-Meier method and log-rank test to generate survival curves. Univariate and multivariate analyses were conducted using the Cox proportional hazard model. Among the participants, the male-to-female ratio was 70:18 and median age was 64.5 years (range, 25-84 years). The numbers of patients with Controlling Nutritional Status score of 0, 1, 2, 3, 4, 5, and 6 were 26 (29.55%), 21 (23.86%), 20 (22.73%), 12 (13.64%), 5 (5.68%), 1 (1.14%), and 3 (3.41%), respectively. The 5-year recurrence rate was 29 out of 88 patients (32.95%). The recurrence-free survival of the high-score group was significantly lower than that of the low-score group (P < 0.001). On univariate analysis, age, smoking history, Controlling Nutritional Status score, depth of tumor invasion, pathological grade, and tumor diameter were related to the prognosis of patients with non-muscle invasive bladder cancer. On multivariate analysis, the Controlling Nutritional Status score (hazard ratio, 4.938; 95% confidence interval, 1.392-17.525; P = 0.013) was an independent factor affecting the recurrence-free survival of patients with non-muscle-invasive bladder cancer. CONCLUSION: Therefore, the Controlling Nutritional Status score could be a simple, cost-effective, and reliable predictor of prognoses among of patients with non-muscle-invasive bladder cancer.
Assuntos
Estado Nutricional , Neoplasias da Bexiga Urinária/mortalidade , Neoplasias da Bexiga Urinária/patologia , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais , Cistectomia , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Invasividade Neoplásica , Recidiva Local de Neoplasia , Avaliação Nutricional , Prognóstico , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Fatores de Risco , Carga Tumoral , Neoplasias da Bexiga Urinária/cirurgiaRESUMO
Chemiluminescence, the generation of light through chemiexcitation as a result of chemical reactions, has emerged as a novel tool for bioimaging and therapy in vivo. Due to the elimination of external optical excitation, it can effectively avoid background autofluorescence existing in fluorescence techniques, providing extremely high signal-to-noise ratios and sensitivity in bioimaging. Furthermore, in situ emitted photons can replace traditional excitation light to construct chemiexcited photodynamic therapy or drug release systems for the monitoring and treatment of deeply seated diseases or tumors. In this tutorial review, we will focus on the recent advancements of chemiluminescent platforms based on luminophore substrates including luminol and its derivatives, cypridina luciferin analogs, peroxyoxalates, and dioxetanes, and systematically summarize the design principles, sensing mechanisms, and bioimaging and therapeutic applications of representative chemiluminescent probes as well as theranostic agents. Finally, the potential challenges and perspectives of chemiluminescent platforms for bioimaging and therapeutics are also discussed.
Assuntos
Diagnóstico por Imagem , Luminescência , Fotoquimioterapia , Animais , Antineoplásicos/farmacologia , Fluorescência , Humanos , Peróxido de Hidrogênio/metabolismo , Limite de Detecção , Camundongos , Fármacos Fotossensibilizantes/farmacologiaRESUMO
Chemiluminescence imaging is imperative for diagnostics and imaging due to its intrinsically high sensitivity. To improve inâ vivo detection of biomarkers, chemiluminophores that simultaneously possess near-infrared (NIR) emission and modular structures amenable to construction of activatable probes are highly desired; however, these are rare. Herein, we report two chemiluminophores with record long NIR emission (>750â nm) via integration of dicyanomethylene-4H-benzothiopyran or dicyanomethylene-4H-benzoselenopyran with dioxetane unit. Caging of the chemiluminophores with different cleavable moieties produces NIR chemiluminescence probes (NCPs) that only produce signals upon reaction with reactive oxygen species or enzymes, for example, ß-galactosidase, with a tissue-penetration depth of up to 2â cm. Thus, this study provides NIR chemiluminescence molecular scaffolds applicable for in vivo turn-on imaging of versatile biomarkers in deep tissues.
Assuntos
Corantes Fluorescentes/química , Imagem Óptica/métodos , Animais , Linhagem Celular Tumoral , Corantes Fluorescentes/metabolismo , Humanos , Raios Infravermelhos , Limite de Detecção , Medições Luminescentes , Camundongos , Camundongos Nus , Neoplasias/diagnóstico por imagem , Espécies Reativas de Oxigênio/análise , Espécies Reativas de Oxigênio/metabolismo , Transplante Heterólogo , beta-Galactosidase/metabolismoRESUMO
Real-time imaging of immunoactivation is imperative for cancer immunotherapy and drug discovery; however, most existing imaging agents possess "always-on" signals and thus have poor signal correlation with immune responses. Herein, renal-clearable near-infrared (NIR) fluorescent macromolecular reporters are synthesized to specifically detect an immunoactivation-related biomarker (granzyme B) for real-time evaluation of cancer immunotherapy. Composed of a peptide-caged NIR signaling moiety linked with a hydrophilic poly(ethylene glycol) (PEG) passivation chain, the reporters not only specifically activate their fluorescence by granzyme B but also passively target the tumor of living mice after systemic administration. Such granzyme B induced in vivo signals of the reporters are validated to correlate well with the populations of cytotoxic T lymphocytes (CD8+) and T helper (CD4+) cells detected in tumor tissues. By virtue of their ideal renal clearance efficiency (60% injected doses at 24 h postinjection), the reporters can be used for optical urinalysis of immunoactivation simply by detecting the status of excreted reporters. This study thus proposes a molecular optical imaging approach for noninvasive evaluation of cancer immunotherapeutic efficacy in living animals.
Assuntos
Imunoterapia/métodos , Neoplasias/terapia , Imagem Óptica/métodos , Espectroscopia de Luz Próxima ao Infravermelho/métodos , Urinálise/métodos , Animais , CamundongosRESUMO
Drug-induced kidney injury (DIKI) is a significant contributor of both acute and chronic kidney injury and remains a major concern in drug development and clinical care. However, current clinical diagnostic methods often fail to accurately and timely detect nephrotoxicity. This study reports the development of activatable molecular urinary reporters (MURs) that are able to specifically detect urinary biomarkers including γ-glutamyl transferase (GGT), alanine aminopeptidase (AAP), and N-acetyl-ß-d-glucosaminidase (NAG). By virtue of their discrete absorption and emission properties, the mixture of MURs can serve as a cocktail sensor for multiplex optical urinalysis in the mouse models of drug-induced acute kidney injury (AKI) and chronic kidney disease (CKD). The MURs cocktail not only detects nephrotoxicity earlier than the tested clinical diagnostic methods in drug-induced AKI and CKD mice models, but also possesses a higher diagnostic accuracy. Therefore, MURs hold great promise for detection of kidney function in both preclinical drug screening and clinical settings.
Assuntos
Acetilglucosaminidase/urina , Injúria Renal Aguda/urina , Antígenos CD13/urina , Insuficiência Renal Crônica/urina , gama-Glutamiltransferase/urina , Acetilglucosaminidase/metabolismo , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/diagnóstico , Animais , Biomarcadores/urina , Antígenos CD13/metabolismo , Células Cultivadas , Cisplatino , Modelos Animais de Doenças , Doxorrubicina , Humanos , Camundongos , Imagem Óptica , Insuficiência Renal Crônica/induzido quimicamente , Insuficiência Renal Crônica/diagnóstico , gama-Glutamiltransferase/metabolismoRESUMO
Drug-induced acute kidney injury (AKI) with a high morbidity and mortality is poorly diagnosed in hospitals and deficiently evaluated in drug discovery. Here, we report the development of molecular renal probes (MRPs) with high renal clearance efficiency for in vivo optical imaging of drug-induced AKI. MRPs specifically activate their near-infrared fluorescence or chemiluminescence signals towards the prodromal biomarkers of AKI including the superoxide anion, N-acetyl-ß-D-glucosaminidase and caspase-3, enabling an example of longitudinal imaging of multiple molecular events in the kidneys of living mice. Importantly, they in situ report the sequential occurrence of oxidative stress, lysosomal damage and cellular apoptosis, which precedes clinical manifestation of AKI (decreased glomerular filtration). Such an active imaging mechanism allows MRPs to non-invasively detect the onset of cisplatin-induced AKI at least 36 h earlier than the existing imaging methods. MRPs can also act as exogenous tracers for optical urinalysis that outperforms typical clinical/preclinical assays, demonstrating their clinical promise for early diagnosis of AKI.
Assuntos
Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/diagnóstico , Imagem Molecular/métodos , Sondas Moleculares , Injúria Renal Aguda/metabolismo , Animais , Biomarcadores/metabolismo , Diagnóstico Precoce , Humanos , Camundongos , Estresse Oxidativo , Espécies Reativas de Oxigênio/metabolismoRESUMO
Optical imaging plays a crucial role in biomedicine. However, due to strong light scattering and autofluorescence in biological tissue between 650-900â nm, conventional optical imaging often has a poor signal-to-background ratio and shallow penetration depth, which limits its ability in deep-tissue inâ vivo imaging. Second near-infrared fluorescence, chemiluminescence, and photoacoustic imaging modalities mitigate these issues by their respective advantages of minimized light scattering, eliminated external excitation, and ultrasound detection. To enable disease detection, activatable molecular probes (AMPs) with the ability to change their second near-infrared fluorescence, chemiluminescence, or photoacoustic signals in response to a biomarker have been developed. This Minireview summarizes the molecular design strategies, sensing mechanisms, and imaging applications of AMPs. The potential challenges and perspectives of AMPs in deep-tissue imaging are also discussed.
Assuntos
Fluorescência , Luminescência , Imagem Molecular/métodos , Sondas Moleculares/química , Técnicas Fotoacústicas/métodos , Espectroscopia de Luz Próxima ao Infravermelho/métodos , Biomarcadores , Humanos , Imagem ÓpticaRESUMO
Bladder cancer (BC) is a prevalent disease with high morbidity and mortality; however, inâ vivo optical imaging of BC remains challenging because of the lack of cancer-specific optical agents with high renal clearance. Herein, a macromolecular reporter (CyP1) was synthesized for real-time near-infrared fluorescence (NIRF) imaging and urinalysis of BC in living mice. Because of the high renal clearance (ca. 94 % of the injection dosage at 24â h post-injection) and its cancer biomarker (APN=aminopeptidaseâ N) specificity, CyP1 can be efficiently transported to the bladder and specially turn on its NIRF signal to report the detection of BC in living mice. Moreover, CyP1 can be used for optical urinalysis, permitting the exâ vivo tracking of tumor progression for therapeutic evaluation and easy translation of CyP2 as an inâ vitro diagnostic assay. This study not only provides new opportunities for non-invasive diagnosis of BC, but also reveals useful guidelines for the development of molecular reporters for the detection of bladder diseases.
Assuntos
Aminopeptidases/metabolismo , Biomarcadores Tumorais/metabolismo , Corantes Fluorescentes/farmacocinética , Substâncias Macromoleculares/farmacocinética , Neoplasias da Bexiga Urinária/diagnóstico por imagem , 2-Hidroxipropil-beta-Ciclodextrina/química , 2-Hidroxipropil-beta-Ciclodextrina/metabolismo , Animais , Transporte Biológico , Carbocianinas/química , Humanos , Substâncias Macromoleculares/administração & dosagem , Substâncias Macromoleculares/urina , Camundongos , Neoplasias Experimentais , Imagem Óptica , Espectroscopia de Luz Próxima ao InfravermelhoRESUMO
Real-time multiplex imaging is imperative to biology and diagnosis but remains challenging for optical modality. Herein, a unimolecular chemo-fluoro-luminescent reporter (CFR) is synthesized for duplex imaging of drug-induced hepatotoxicity (DIH), a long-term medical concern. CFR simultaneously detects superoxide anion (O2â¢-) and caspase-3 (casp3) through respective activation of its independent chemiluminescence and near-infrared fluorescence channels. Such a crosstalk-free duplex imaging capability of CFR enables longitudinal measurement of two correlated biomolecular events (oxidative stress and cellular apoptosis) during the progression of DIH, identifying O2â¢- as an earlier biomarker for detection of DIH both in vitro and in vivo. Moreover, CFR detects DIH 17.5 h earlier than histological changes. Thus, our study not only develops a sensitive optical reporter for early detection of DIH but also provides a general molecular design strategy for duplex imaging.
Assuntos
Doença Hepática Induzida por Substâncias e Drogas/diagnóstico por imagem , Fígado/diagnóstico por imagem , Substâncias Luminescentes/química , Animais , Caspase 3/análise , Fluorescência , Corantes Fluorescentes/química , Fígado/efeitos dos fármacos , Luminescência , Camundongos , Imagem Óptica/métodos , Superóxidos/análiseRESUMO
Therapeutic enzymes hold great promise for cancer therapy; however, in vivo remote control of enzymatic activity to improve their therapeutic specificity remains challenging. This study reports the development of an organic semiconducting pro-nanoenzyme (OSPE) with a photoactivatable feature for metastasis-inhibited cancer therapy. Upon near-infrared (NIR) light irradiation, this pro-nanoenzyme not only generates cytotoxic singlet oxygen (1O2) for photodynamic therapy (PDT), but also triggers a spontaneous cascade reaction to induce the degradation of ribonucleic acid (RNA) specifically in tumor microenvironment. More importantly, OSPE-mediated RNA degradation is found to downregulate the expression of metastasis-related proteins, contributing to the inhibition of metastasis after treatment. Such a photoactivated and cancer-specific synergistic therapeutic action of OSPE enables complete inhibition of tumor growth and lung metastasis in mouse xenograft model, which is not possible for the counterpart PDT nanoagent. Thus, our study proposes a phototherapeutic-proenzyme approach toward complete-remission cancer therapy.
Assuntos
Antineoplásicos/farmacologia , Ácidos Borônicos/farmacologia , Neoplasias Mamárias Experimentais/tratamento farmacológico , Nanopartículas/química , Fotoquimioterapia , Fármacos Fotossensibilizantes/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Ácidos Borônicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Raios Infravermelhos , Neoplasias Mamárias Experimentais/patologia , Camundongos , Estrutura Molecular , Imagem Óptica , Tamanho da Partícula , Processos Fotoquímicos , Fármacos Fotossensibilizantes/síntese química , Fármacos Fotossensibilizantes/química , Semicondutores , Oxigênio Singlete/química , Oxigênio Singlete/farmacologiaRESUMO
Real-time imaging of kidney function is important to assess the nephrotoxicity of drugs and monitor the progression of renal diseases; however, it remains challenging because of the lack of optical agents with high renal clearance and high signal-to-background ratio (SBR). Herein, a second near-infrared (NIR-II) fluorescent molecular semiconductor (CDIR2) is synthesized for real-time imaging of kidney dysfunction in living mice. CDIR2 not only has a high renal clearance efficiency (≈90 % injection dosage at 24â h post-injection), but also solely undergoes glomerular filtration into urine without being reabsorbed and secreted in renal tubules. Such a unidirectional renal clearance pathway of CDIR2 permits real-time monitoring of kidney dysfunction in living mice upon nephrotoxic exposure. Thus, this study not only introduces a molecular renal probe but also provides useful molecular guidelines to increase the renal clearance efficiency of NIR-II fluorescent agents.
Assuntos
Corantes Fluorescentes/farmacocinética , Nefropatias/diagnóstico por imagem , Rim/diagnóstico por imagem , Imagem Óptica/métodos , Semicondutores , Espectroscopia de Luz Próxima ao Infravermelho/métodos , Animais , Linhagem Celular , Feminino , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/química , Rim/metabolismo , Nefropatias/metabolismo , Testes de Função Renal , Taxa de Depuração Metabólica , Camundongos , Camundongos NusRESUMO
Despite its high morbidity and mortality, contrast-induced acute kidney injury (CIAKI) remains a diagnostic dilemma because it relies on inâ vitro detection of insensitive late-stage blood and urinary biomarkers. We report the synthesis of an activatable duplex reporter (ADR) for real-time inâ vivo imaging of CIAKI. ADR is equipped with chemiluminescence and near-infrared fluorescence (NIRF) signaling channels that can be activated by oxidative stress (superoxide anion, O2.- ) and lysosomal damage (N-acetyl-ß-d-glucosaminidase, NAG), respectively. By virtue of its high renal clearance efficiency (80 % injected doses after 24â h injection), ADR detects sequential upregulation of O2.- and NAG in the kidneys of living mice prior to a significant decrease in glomerular filtration rate (GFR) and tissue damage in the course of CIAKI. ADR outperforms the typical clinical assays and detects CIAKI at least 8â h (NIRF) and up to 16â h (chemiluminescence) earlier.