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1.
Nano Lett ; 21(18): 7862-7869, 2021 09 22.
Artigo em Inglês | MEDLINE | ID: mdl-34494442

RESUMO

Blocking energy metabolism of cancer cells and simultaneously stimulating the immune system to perform immune attack are significant for cancer treatment. However, how to potently deliver different drugs with these functions remains a challenge. Herein, we synthesized a nanoprodrug formed by a F127-coated drug dimer to inhibit glycolysis of cancer cells and alleviate the immunosuppressive microenvironment. The dimer was delicately constructed to connect lonidamine (LND) and NLG919 by a disulfide bond which can be cleaved by excess GSH to release two drugs. LND can decrease the expression of hexokinase II and destroy mitochondria to restrain glycolysis for energy supply. NLG919 can reduce the accumulation of kynurenine and the number of regulatory T cells, thus alleviating the immunosuppressive microenvironment. Notably, the consumption of GSH by disulfide bond increased the intracellular oxidative stress and triggered immunogenic cell death of cancer cells. This strategy can offer more possibilities to explore dimeric prodrugs for synergistic cancer therapy.


Assuntos
Antineoplásicos , Neoplasias , Pró-Fármacos , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Glicólise , Morte Celular Imunogênica , Imunossupressão , Neoplasias/tratamento farmacológico , Polímeros/uso terapêutico , Pró-Fármacos/uso terapêutico
2.
Theranostics ; 11(16): 7869-7878, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34335969

RESUMO

Goals: Chemotherapy, the most conventional modality for cancer therapy, usually brings serious side effects because of the low cancer-therapeutic specificity and bioavailability. It is of great significance for cancer treatment to develop new effective strategies to regulate biochemical reactions in organelles, enhance the specificity of chemotherapeutic drugs and reduce their side effects. Methods: We report herein a zeolitic imidazole framework-90 (ZIF-90) based nanoplatform, which was used to initiate a series of mitochondrial cascade reactions using ATP as a molecular switch for cancer therapy. The thioketal linked camptothecin (camptothecin prodrug, TK-CPT) and 2-Methoxyestradiol (2-ME) were encapsulated into the pores of ZIF-90 nanoparticles using a simple one-pot method, and the nanoplatform was finally coated with a layer of homologous cell membrane. Results: Mitochondrial ATP can efficiently degrade ZIF-90 and then release the loaded 2-ME and CPT prodrugs. 2-ME can inhibit the activity of superoxide dismutase (SOD), which induces the up-regulation of reactive oxygen species (ROS) in situ. The thioketal linkers in CPT prodrug can respond to ROS, thereby achieving subsequent release of parent CPT drug. This cascade of reactions can lead to prolonged high oxidative stress and cause continuous cancer cell apoptosis, due to the increased ROS level and the liberation of CPT. Conclusion: We constructed an ATP-triggered strategy using nanoscale ZIF-90 to initiate mitochondrial cascade reactions for cancer therapy. The ZIF-90 based nanoplatform exhibited low cytotoxicity, good mitochondria-targeting ability, and excellent therapeutic effect. In vivo experiments demonstrated that the growth of tumor can be efficiently inhibited in a mouse model. This ATP-triggered strategy to induce mitochondrial biochemical reactions offers more possibilities for developing organelle-targeted therapeutic platforms.


Assuntos
Antineoplásicos/uso terapêutico , Sistemas de Liberação de Medicamentos/métodos , Zeolitas/química , Trifosfato de Adenosina/química , Trifosfato de Adenosina/metabolismo , Animais , Antineoplásicos/farmacologia , Disponibilidade Biológica , Linhagem Celular Tumoral , China , Liberação Controlada de Fármacos/fisiologia , Imidazóis/química , Imidazóis/metabolismo , Imidazóis/farmacologia , Camundongos , Mitocôndrias/metabolismo , Nanopartículas/administração & dosagem , Neoplasias/metabolismo , Pró-Fármacos/química , Espécies Reativas de Oxigênio/metabolismo , Zeolitas/metabolismo , Zeolitas/farmacologia
3.
Chem Commun (Camb) ; 57(54): 6584-6595, 2021 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-34137400

RESUMO

Taking advantage of activatable and imaging-guided properties, stimuli-activated molecular photothermal agents (MPTAs) have drawn great attention in photothermal therapy (PTT) over the past decades. In this review, the recent progress in the study of stimuli-activated MPTAs is summarized from different stimuli, including pH, bioactive small molecules, and enzymes. The features and challenges of stimuli-activated MPTAs are also discussed. This review aims to motivate readers to design and synthesise more efficient MPTAs.


Assuntos
Hipertermia Induzida/métodos , Neoplasias/terapia , Fototerapia/métodos , Animais , Humanos , Neoplasias/patologia
4.
ACS Sens ; 6(5): 1949-1955, 2021 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-33905657

RESUMO

Nucleic acids as the important tumor markers play a crucial role in the identification of cancer. Various kinds of probes such as gold nanoparticles and graphene oxide have been explored to detect different nucleic acid markers. However, the existing probes are mostly used to detect a single tumor marker and susceptible to harsh conditions in the complex and dynamic physiological environment, which may lead to false positive results and greatly limit the sensing performance of the probe. Herein, a powerful and reliable Au-Se probe was developed for high-fidelity imaging of two cancer markers simultaneously in living cells. Compared with the traditional nucleic acid probe based on the Au-S bond, this probe was more stable against biological thiols and could effectively distinguish normal cells and cancer cells to avoid false positive results, which is more suitable for imaging in a complex physiological environment. This strategy will provide more valuable insights into designing and exploring novel biosensors in the future.


Assuntos
Técnicas Biossensoriais , Nanopartículas Metálicas , Ouro , Sondas de Ácido Nucleico , Compostos de Sulfidrila
5.
Angew Chem Int Ed Engl ; 60(24): 13564-13568, 2021 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-33783939

RESUMO

Photothermal therapy usually requires a high power density to activate photothermal agent for effective treatment, which inevitably leads to damage to normal tissues and inflammation in tumor tissues. Herein, we rationally design a protein-binding strategy to build a molecular photothermal agent for photothermal ablation of tumor. The synthesized photothermal agent can covalently bind to the thiol groups on the intracellular proteins. The heat generated by the photothermal agent directly destroyed the bioactive proteins in the cells, effectively reducing the heat loss and the molecular leakage. Under a low power density of 0.2 W cm-2 , the temperature produced by the photothermal agent was sufficient to induce apoptosis. In vitro and in vivo experiments showed that the therapeutic effect of photothermal therapy can be efficiently improved with the protein-binding strategy.


Assuntos
Neoplasias/terapia , Compostos Orgânicos/química , Terapia Fototérmica/métodos , Proteínas/química , Animais , Linhagem Celular , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Humanos , Lasers , Maleimidas/química , Maleimidas/metabolismo , Maleimidas/farmacologia , Maleimidas/uso terapêutico , Camundongos , Compostos Orgânicos/metabolismo , Compostos Orgânicos/farmacologia , Compostos Orgânicos/uso terapêutico , Proteínas/metabolismo
6.
Chem Commun (Camb) ; 56(63): 8968-8971, 2020 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-32638761

RESUMO

A lung cancer diagnostic kit (LCDK) with the advantages of low cost, easy operation and high sensitivity for the rapid diagnosis of lung cancer was developed. The proposed LCDK is able to noninvasively discriminate lung cancer using clinical salivary and urine samples in a short period of time.


Assuntos
Exossomos/metabolismo , Neoplasias Pulmonares/diagnóstico , MicroRNAs/análise , Testes Imediatos , Saliva/metabolismo , Aptâmeros de Nucleotídeos/química , Aptâmeros de Nucleotídeos/metabolismo , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/urina , Exossomos/genética , Humanos , Neoplasias Pulmonares/genética , MicroRNAs/urina , Nanopartículas/química
7.
Chem Sci ; 11(31): 8055-8072, 2020 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-34123080

RESUMO

Photothermal therapy, in which light is converted into heat and triggers local hyperthermia to ablate tumors, presents an inherently specific and noninvasive treatment for tumor tissues. In this area, the development of efficient photothermal agents (PTAs) has always been a central topic. Although many efforts have been made on the investigation of novel molecular architectures and photothermal materials over the past decades, PTAs can cause severe damage to normal tissues because of the poor tumor aggregate ability and high irradiation density. Recently, dual-targeted photothermal agents (DTPTAs) provide an attractive strategy to overcome these problems and enhance cancer therapy. DTPTAs are functionalized with two classes of targeting units, including tumor environment targeting sites, tumor targeting sites and organelle targeting sites. In this perspective, typical targeted ligands and representative examples of photothermal therapeutic agents with dual-targeted properties are systematically summarized and recent advances using DTPTAs in tumor therapy are highlighted.

8.
Chem Commun (Camb) ; 55(76): 11426-11429, 2019 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-31482870

RESUMO

Highly regioselective Markovnikov hydrofunctionalization of alkenes was successfully realized via photoredox catalysis by introducing a urea group and fine tuning the hydrogen atom transfer catalysts. The anti-Markovnikov hydroamination of alkenes was also achieved with high yields and stereoselectivities in this work.

9.
Org Biomol Chem ; 17(26): 6351-6354, 2019 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-31215946

RESUMO

A range of 3,3-disubstituted oxindoles accessed using para-quinone methides derived from isatins with thiols were used for the formation of unsymmetrical disulfides, and 3,3-disubstituted oxindoles with a chiral quaternary carbon center and unsymmetric disulfides could also be directly obtained with high selectivities catalyzed by chiral phosphines in one step.

10.
Chem Commun (Camb) ; 54(84): 11965-11968, 2018 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-30289138

RESUMO

Utilizing the oxidation/elimination tandem reaction of the α-phenylseleno carbonyl moiety, a two-photon fluorescent probe for ratiometric visualization of hypochlorous acid was developed. Its superior sensing performance and practical applications were well demonstrated.

11.
Chem Commun (Camb) ; 54(78): 10989-10992, 2018 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-30211917

RESUMO

An application of H-bonding interactions for directing the α-C-H oxidation of amines to amides and amino-ketones catalyzed by an organic photocatalyst is reported. The high efficiency of this method is demonstrated by the aerobic oxidation of pyrrolidines, diarylamines and benzylamines bearing urea groups with high yields and a wide substrate scope.

12.
Biochim Biophys Acta Mol Basis Dis ; 1863(12): 3128-3141, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28844956

RESUMO

OBJECTIVE: Obesity is associated with metabolic disorder and chronic inflammation that plays a crucial role in cardiovascular diseases. IL-6 is involved in regulating obesity-related lipid metabolism and inflammation. In this study, we sought to determine the role of IL-6 in high-fat diet (HFD)-induced cardiomyopathy and explore the signaling pathway. METHODS: Female, 5-week-old IL-6 knockout (KO) and littermate mice were fed a normal diet (ND, 10% fat) or HFD (45% fat) for 14 weeks. At the end of treatment, cardiac function was assessed by echocardiography. Adipose tissues and plasma were collected for further measurement. Immunohistology of CD68 was performed to detect inflammation in the heart. Masson's trichrome staining and Oil Red O staining was applied to evaluated cardiac fibrosis and lipid accumulation. Real-time PCR and Western immunoblotting analyses on heart tissue were used to explore the underlying mechanism. RESULTS: IL-6 KO mice displayed increased insulin resistance compared to WT mice at baseline. When fed HFD, IL-6 KO mice showed decreased gains in body weight and fat mass, increased insulin resistance relative to IL-6 KO mice feed ND. Furthermore, IL-6 KO mice developed cardiac dysfunction during HFD-induced obesity. Histological analysis suggested increased lipid accumulation, fibrosis and inflammation without affecting cardiac morphology during HFD treatment in the heart of IL-6 KO mice. Finally, IL-6 deficiency increased the phosphorylation of AMPK and ACC in the heart during HFD-induced obesity. CONCLUSION: Our results suggest that IL-6 contributes to limit lipid metabolic disorder, cardiac hypertrophy, fibrosis, inflammation and myocardium lipotoxicity during HFD-induced obesity.


Assuntos
Interleucina-6/deficiência , Obesidade/metabolismo , Tecido Adiposo/metabolismo , Animais , Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/metabolismo , Cardiomegalia/metabolismo , Cardiomiopatias/metabolismo , Cardiomiopatias/fisiopatologia , Dieta Hiperlipídica , Ácidos Graxos/metabolismo , Feminino , Fibrose/metabolismo , Fibrose/fisiopatologia , Técnicas de Inativação de Genes , Coração/fisiopatologia , Inflamação/metabolismo , Inflamação/patologia , Resistência à Insulina , Interleucina-6/genética , Interleucina-6/metabolismo , Metabolismo dos Lipídeos , Camundongos , Camundongos Knockout , Miocárdio/metabolismo , Miocárdio/patologia , Obesidade/fisiopatologia , Fosforilação
13.
Chem Commun (Camb) ; 53(69): 9644-9647, 2017 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-28812065

RESUMO

A novel method for concisely synthesizing 1,2,4-triazolines via [3+2] cyclization under visible light is reported. These compounds can be easily converted into 1,2,4-triazoles under basic or photoredox conditions. The application of the 1,2,4-triazoles was also investigated via mild operations.

14.
IEEE Trans Pattern Anal Mach Intell ; 38(10): 2010-23, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-26660704

RESUMO

Cross-modal retrieval has recently drawn much attention due to the widespread existence of multimodal data. It takes one type of data as the query to retrieve relevant data objects of another type, and generally involves two basic problems: the measure of relevance and coupled feature selection. Most previous methods just focus on solving the first problem. In this paper, we aim to deal with both problems in a novel joint learning framework. To address the first problem, we learn projection matrices to map multimodal data into a common subspace, in which the similarity between different modalities of data can be measured. In the learning procedure, the l21-norm penalties are imposed on the projection matrices separately to solve the second problem, which selects relevant and discriminative features from different feature spaces simultaneously. A multimodal graph regularization term is further imposed on the projected data,which preserves the inter-modality and intra-modality similarity relationships.An iterative algorithm is presented to solve the proposed joint learning problem, along with its convergence analysis. Experimental results on cross-modal retrieval tasks demonstrate that the proposed method outperforms the state-of-the-art subspace approaches.

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