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As a promising gene therapy strategy, controllable small molecule-mRNA covalent modification in tumor cells could be initiated by singlet oxygen (1O2) to complete the modification process. However, in vivo generation of 1O2 is usually dependent on excitation of external light, and the limited light penetration of tissues greatly interferes the development of deep tumor phototherapy. Here, we constructed a tumor-targeting nano-micelle for the spontaneous intracellular generation of 1O2 without the need for external light, and inducing a high level of covalent modification of mRNA in tumor cells. Luminal and Ce6 were chemically bonded to produce 1O2 by chemiluminescence resonance energy transfer (CRET) triggered by high levels of hydrogen peroxide (H2O2) in the tumor microenvironment. The sufficient 1O2 oxidized the loaded furan to highly reactive dicarbonyl moiety, which underwent cycloaddition reaction with adenine (A), cytosine (C) or guanine (G) on the mRNA for interfering with the tumor cell protein expression, thereby inhibiting tumor progression. In vitro and in vivo experiments demonstrated that this self-initiated gene therapy nano-micelle could induce covalent modification of mRNA by 1O2 without external light, and the process could be monitored in real time by fluorescence imaging, which provided an effective strategy for RNA-based tumor gene therapy.
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Appendage regeneration relies on the formation of blastema, a heterogeneous cellular structure formed at the injury site. However, little is known about the early injury-activated signaling pathways that trigger blastema formation during appendage regeneration. Here, we provide compelling evidence that the extracellular signal-regulated kinase (ERK)-activated casein kinase 2 (CK-2), which has not been previously implicated in appendage regeneration, triggers blastema formation during leg regeneration in the American cockroach, Periplaneta americana. After amputation, CK-2 undergoes rapid activation through ERK-induced phosphorylation within blastema cells. RNAi knockdown of CK-2 severely impairs blastema formation by repressing cell proliferation through down-regulating mitosis-related genes. Evolutionarily, the regenerative role of CK-2 is conserved in zebrafish caudal fin regeneration via promoting blastema cell proliferation. Together, we find and demonstrate that the ERK-activated CK-2 triggers blastema formation in both cockroach and zebrafish, helping explore initiation factors during appendage regeneration.
Assuntos
Regeneração , Peixe-Zebra , Animais , Peixe-Zebra/metabolismo , Regeneração/genética , Cicatrização , Transdução de Sinais/genética , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismoRESUMO
Previous studies have demonstrated that high physiological levels of reactive oxygen species induce pupal diapause and extend lifespan in the moth Helicoverpa armigera. This has been shown to occur via protein arginine methyltransferase 1 (PRMT1) blockade of Akt-mediated phosphorylation of the transcription factor FoxO, after which activated FoxO promotes the initiation of diapause. However, it is unclear how PRMT1 is activated upstream of FoxO activity. Here, we show that high reactive oxygen species levels in the brains of H. armigera diapause-destined pupae activate the expression of c-Jun N-terminal kinase, which subsequently activates the transcription factor cAMP-response element binding protein. We show that cAMP-response element binding protein then directly binds to the PRMT1 promoter and upregulates its expression to prevent Akt-mediated FoxO phosphorylation and downstream FoxO nuclear localization. This novel finding that c-Jun N-terminal kinase promotes FoxO nuclear localization in a PRMT1-dependent manner to regulate pupal diapause reveals a complex regulatory mechanism in extending the healthspan of H. armigera.
Assuntos
Mariposas , Proteína-Arginina N-Metiltransferases , Animais , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Longevidade , Mariposas/fisiologia , Proteína-Arginina N-Metiltransferases/genética , Proteína-Arginina N-Metiltransferases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Fatores de Transcrição/metabolismo , Proteínas de Insetos/genética , Proteínas de Insetos/metabolismo , Pupa , DiapausaRESUMO
Reactive oxygen species (ROS) are considered a major cause of ageing and ageing-related diseases through protein carbonylation. Little is known about the molecular mechanisms that confer protection against ROS. Here, we observed that, compared with nondiapause-destined pupae, high protein carbonyl levels are present in the brains of diapause-destined pupae, which is a 'non-ageing' phase in the moth Helicoverpa armigera. Protein carbonyl levels respond to ROS and decrease metabolic activity to induce diapause in order to extend lifespan. However, protein carbonylation in the brains of diapause-destined pupae still occurs at a physiological level compared to young adult brains. We find that ROS activate Akt, and Akt then phosphorylates the transcription factor CREB to facilitate its nuclear import. CREB binds to the promoter of carbonyl reductase 1 (CBR1) and regulates its expression. High CBR1 levels reduce protein carbonyl levels to maintain physiological levels. This is the first report showing that the moth brain can naturally control protein carbonyl levels through a distinct ROS-Akt-CREB-CBR1 pathway to extend lifespan.
Assuntos
Mariposas , Proteínas Proto-Oncogênicas c-akt , Animais , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Carbonil Redutase (NADPH) , Longevidade/fisiologia , Carbonilação Proteica , Mariposas/genética , Mariposas/metabolismo , Pupa/metabolismoRESUMO
Diapause is a form of dormancy used widely by insects to survive adverse seasons. Previous studies have demonstrated that forkhead box O (FoxO) is activated during pupal diapause initiation in the moth Helicoverpa armigera. However, it is unclear how FoxO induces diapause. Here, we show that knockout of FoxO causes H. armigera diapause-destined pupae to channel into nondiapause, indicating that FoxO is a master regulator that induces insect diapause. FoxO activates the ubiquitin-proteasome system (UPS) by promoting ubiquitin c (Ubc) expression via directly binding to the Ubc promoter. Activated UPS decreases transforming growth factor beta (TGFß) receptor signaling via ubiquitination to block developmental signaling to induce diapause. This study significantly advances the understanding of insect diapause by uncovering the detailed molecular mechanism of FoxO.
Assuntos
Diapausa de Inseto , Diapausa , Animais , Fator de Crescimento Transformador beta , Pupa , Transdução de Sinais , Receptores de Fatores de Crescimento Transformadores beta , Ubiquitina , Complexo de Endopeptidases do ProteassomaRESUMO
Inefficient tumour treatment approaches often cause fatal tumour metastases. Here, we report a biomimetic multifunctional nanoplatform explicitly engineered with a Co-based metal organic framework polydopamine heterostructure (MOF-PDA), anethole trithione (ADT), and a macrophage membrane. Co-MOF degradation in the tumour microenvironment releases Co2+, which results in the downregulation of HSP90 expression and the inhibition of cellular heat resistance, thereby improving the photothermal therapy effect of PDA. H2S secretion after the enzymatic hydrolysis of ADT leads to high-concentration gas therapy. Moreover, ADT changes the balance between nicotinamide adenine dinucleotide/flavin adenine dinucleotide (NADH/FAD) during tumour glycolysis. ATP synthesis is limited by NADH consumption, which triggers a certain degree of tumour growth inhibition and results in starvation therapy. Potentiated 2D/3D autofluorescence imaging of NADH/FAD is also achieved in liquid nitrogen and employed to efficiently monitor tumour therapy. The developed biomimetic nanoplatform provides an approach to treat orthotopic tumours and inhibit metastasis.
Assuntos
Materiais Biomiméticos , Hipotermia , Neoplasias , Biomimética , Metabolismo Energético , Flavina-Adenina Dinucleotídeo/metabolismo , Humanos , NAD/metabolismo , Neoplasias/patologia , Microambiente TumoralRESUMO
It is vital for physicians and persons with chronic myeloid leukemia (CML) to accurately predict the likelihood of achieving a major molecular response (MMR) and a deep molecular response (DMR; at least MR4) at the start of imatinib-therapy, which could help in decision making of treatment goals and strategies. To answer this question, we interrogated data from 1369 consecutive subjects with chronic phase CML receiving initial imatinib-therapy to identify predictive co-variates. Subjects were randomly-assigned to training (n = 913) and validation (n = 456) datasets. Male sex, higher WBC concentration, lower haemoglobin concentration, higher percentage blood blasts and larger spleen size were significantly-associated with lower cumulative incidences of MMR and MR4 in training dataset. Using Fine-Gray model, we developed the predictive scoring systems for MMR and MR4 which classified subjects into the low-, intermediate- and high-risk cohorts with significantly-different cumulative incidences of MMR and MR4 with good predictive discrimination and accuracy in training and validation cohorts with high area under the receiver-operator characteristic curve (AUROC) values. These data may help physicians decide appropriateness of initial imatinib therapy.
Assuntos
Antineoplásicos , Leucemia Mielogênica Crônica BCR-ABL Positiva , Leucemia Mieloide de Fase Crônica , Antineoplásicos/uso terapêutico , Humanos , Mesilato de Imatinib/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mieloide de Fase Crônica/tratamento farmacológico , Leucemia Mieloide de Fase Crônica/genética , Masculino , Inibidores de Proteínas Quinases/uso terapêutico , Resultado do TratamentoRESUMO
We interrogated data from 278 consecutive subjects with chronic myeloid leukaemia (CML) presenting in accelerated phase diagnosed by European LeukemiaNet (ELN) criteria receiving initial imatinib (n = 187) or a 2nd-generation tyrosine kinase-inhibitor (2G-TKI; n = 91). In multi-variable analyses, blood and/or bone marrow blasts ≥15% (Hazard ratio [HR] = 3.7 [1.6, 8.5], p = 0.003) and blood basophils <3% (HR = 4.6 [2.0, 10.7], p < 0.001) were significantly-associated with worse transformation-free survival (TFS). Age ≥60 years (HR = 4.3 [1.7, 11.4], p = 0.003), platelet concentration <230 × 10E + 9/L (HR = 4.7 [2.0, 10.7], p < 0.001) and blood and/or bone marrow blasts ≥9% (HR = 3.9 [1.7, 8.7], p = 0.001) were significantly-associated with worse survival. Based on number of adverse prognostic co-variates of TFS and survival, respectively, subjects were classified into the low- (none), intermediate- (one) and high-risk (≥2) cohorts with significant difference in TFS and survival (all p < 0.001). In propensity-score matching analysis subjects initially receiving a 2G-TKI had higher cumulative incidences of cytogenetic and molecular responses but similar TFS and survival to those receiving imatinib. Our data should help inform physicians treating person with CML initially presenting in accelerated phase.
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Leucemia Mielogênica Crônica BCR-ABL Positiva , Humanos , Mesilato de Imatinib/uso terapêutico , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Tirosina Quinases , Resultado do TratamentoRESUMO
Data from 1,364 consecutive subjects with chronic-phase chronic myeloid leukemia (CML) receiving initial imatinib-therapy were interrogated to identify co-variates predicting therapy failure. Subjects were randomly divided into training (n = 908) and validation datasets (n = 456). In the training dataset, WBC count ≥120 × 10E + 9/L, haemoglobin concentration <115 g/L, blood basophils ≥12% and European Treatment and Outcome Study for CML Long-Term Survival (ELTS) risk score were significantly-associated with failure-free survival (FFS). Each co-variate was assigned 1 point to develop the imatinib-therapy failure (IMTF) model except ELTS high-risk category which was assigned 2 points based on multi-variable regression coefficients. Area under receiver-operator characteristic curve values in the IMTF model for 1-, 3- and 5-year FFS were 0.79-0.84 in the training dataset and 0.78-0.85 in the validation dataset. Calibration plots showed high agreement between predicted and observed outcomes. Decision curve analyses indicated subjects benefited from clinical use of this model. Cumulative incidences of imatinib-therapy failure and probabilities of FFS among the 5 risk cohorts (very low-, low-, intermediate-, high- and very high-risk) using the IMTF model were significantly different (all p values < 0.001). The IMTF model also correlated with probabilities of progression-free survival and survival (all p values < 0.001). These data should help physicians optimize TKI-therapy strategy at diagnosis in persons with chronic phase CML.
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Antineoplásicos , Leucemia Mielogênica Crônica BCR-ABL Positiva , Leucemia Mieloide de Fase Crônica , Antineoplásicos/uso terapêutico , Humanos , Mesilato de Imatinib/uso terapêutico , Leucemia Mieloide de Fase Crônica/tratamento farmacológico , Intervalo Livre de Progressão , Inibidores de Proteínas Quinases/uso terapêutico , Resultado do TratamentoRESUMO
Data from 1661 consecutive subjects with chronic-phase chronic myeloid leukemia (CML) receiving initial imatinib (n = 1379) or a 2nd-generation tyrosine-kinase inhibitor (2G-TKI; n = 282) were interrogated to determine whether the Sokal or European Treatment and Outcome Study for CML (EUTOS) long-term survival (ELTS) scores were more accurate responses and outcome predictors. Both scores predicted probabilities of achieving complete cytogenetic response (CCyR), major molecular response (MMR), failure- and progression-free survivals (FFS, PFS), and survival in all subjects and those receiving imatinib therapy. However, the ELTS score was a better predictor of MR4, MR4.5, and CML-related survival than the Sokal score. In subjects receiving 2G-TKI therapy, only the ELTS score accurately predicted probabilities of CCyR, MMR, MR4, FFS, and PFS. In the propensity score matching, subjects classified as intermediate risk by the ELTS score receiving a 2G-TKI had better responses (p < 0.001~0.061), FFS (p = 0.002), and PFS (p = 0.03) but not survival. Our data suggest better overall prediction accuracy for the ELTS score compared with the Sokal score in CML patients, especially those receiving 2G-TKIs. People identified as intermediate risk by the ELTS score may benefit more from initial 2G-TKI therapy in achieving surrogate endpoints but not survival, especially when a briefer interval to stopping TKI therapy is the therapy objective.
Assuntos
Leucemia Mielogênica Crônica BCR-ABL Positiva/mortalidade , Nomogramas , Inibidores de Proteínas Quinases/uso terapêutico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Taxa de Sobrevida , Adulto JovemRESUMO
Previous studies have shown that high physiological levels of reactive oxygen species (ROS) in the brain promote pupal diapause, which extends the pupal lifespan. However, the molecular mechanisms of ROS generation are unclear. In this paper, we found that mitochondrial ROS (mtROS) levels in the brains of Helicoverpa armigera diapause-destined pupae (DP) were higher and that the expression of cytochrome oxidase subunit IV (COXIV) was lower than in NP. In addition, downregulating COXIV caused mitochondrial dysfunction which elevated mtROS levels. Protein kinase A (PKA) was downregulated in DP, which led to the downregulated expression of the mitochondrial transcription factor TFAM. Low TFAM activity failed to promote COXIV expression and resulted in the high ROS levels that induced diapause. In addition, low sirtuin 2 expression suppressed glucose-6-phosphate dehydrogenase (G6PD) deacetylation at K382, which led to reduced G6PD activity and low NADPH levels, thereby maintaining high levels of ROS. Two proteins, COXIV and G6PD, thus play key roles in the elevated accumulation of ROS that induce diapause and extend the pupal lifespan.
Assuntos
Proteínas Quinases Dependentes de AMP Cíclico/genética , Diapausa/genética , Complexo IV da Cadeia de Transporte de Elétrons/genética , Glucosefosfato Desidrogenase/genética , Sirtuína 2/genética , Acetilação , Animais , Encéfalo/metabolismo , Regulação da Expressão Gênica , Mitocôndrias/genética , Mitocôndrias/metabolismo , Mariposas/genética , Mariposas/metabolismo , Pupa/genética , Pupa/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Sirtuína 2/metabolismo , Fatores de Transcrição/genéticaRESUMO
Ameliorated therapy based on the tumor microenvironment is becoming increasingly popular, yet only a few methods have achieved wide recognition. Herein, targeting multifunctional hydrophilic nanomicelles, AgBiS2@DSPE-PEG2000-FA (ABS-FA), were obtained and employed for tumor treatment. In a cascade amplification mode, ABS-FA exhibited favorable properties of actively enhancing computed tomography/infrared (CT/IR) imaging and gently relieving ambient oxygen concentration by cooperative photothermal and sonodynamic therapy. Compared with traditional Bi2S3 nanoparticles, the CT imaging capability of the probe was augmented (43.21%), and the photothermal conversion efficiency was increased (33.1%). Furthermore, remarkable ultrasonic dynamic features of ABS-FA were observed, with increased generation of reactive oxygen species (24.3%) being obtained compared to Ce6, a commonly used sonosensitizer. Furthermore, ABS-FA exhibited obvious inhibitory effects on HeLa cell migration at 6 µg/mL, which to some extent, demonstrated its suppressive effect on tumor growth. A lower dose, laser and ultrasonic power, and shorter processing time endowed ABS-FA with excellent photothermal and sonodynamic effects. By mild cascade mode, the hypoxic condition of the tumor site was largely improved, and a suitable oxygen-rich environment was provided, thereby endowing ABS-FA with a superior synergistically enhanced treatment effect compared with the single-mode approach, which ultimately realized the purpose of "one injection, multiple treatment". Moreover, our data showed that ABS-FA was given with a biological safety profile while harnessing in vivo. Taken together, as a synergistically enhanced medical diagnosis and treatment method, the one-for-all nanoplatform will pave a new avenue for further clinical applications.
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Antineoplásicos/farmacologia , Ácido Fólico/farmacologia , Neoplasias Experimentais/terapia , Terapia Fototérmica , Compostos de Prata/farmacologia , Sulfetos/farmacologia , Terapia por Ultrassom , Animais , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Ácido Fólico/química , Células HeLa , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias Experimentais/patologia , Tamanho da Partícula , Compostos de Prata/química , Sulfetos/química , Propriedades de SuperfícieRESUMO
Diapause is a complex physiological response that allows insects to survive unfavorable environmental conditions, and many signaling pathways participate in regulating this process. However, little is known about TOR signaling in the regulation of diapause. In this study, we found that the TOR pathway-related proteins TOR and Raptor are expressed at low levels in the brains of diapause-destined pupae of Helicoverpa armigera, consistent with a previous report that TOR signaling is associated with development. Interestingly, another TOR signaling-related protein, p-S6K, was increased in the brains of diapause-destined pupae. Our results showed that p-S6K in the brains of diapause-destined pupae can respond to the upstream signals reactive oxygen species (ROS) and AKT and that S6K activates the level of CREB, which binds to the HIF-1α promoter and increases its expression. Previous study has shown that HIF-1α levels elevated by ROS in the brains of diapause-destined pupae cause low mitochondrial activity for insect diapause. Thus, p-S6K in response to ROS/AKT regulates HIF-1α via activating transcription factor CREB for diapause initiation.
Assuntos
Diapausa de Inseto/genética , Proteínas de Insetos/genética , Mariposas/genética , Proteínas Quinases S6 Ribossômicas/genética , Transdução de Sinais , Animais , Proteínas de Insetos/metabolismo , Larva/genética , Larva/crescimento & desenvolvimento , Larva/metabolismo , Mariposas/crescimento & desenvolvimento , Mariposas/metabolismo , Proteínas Quinases S6 Ribossômicas/metabolismoRESUMO
Non-invasive sonodynamic therapy (SDT) was developed because of its advantages of high penetration depth and low side effects; however, tumor hypoxia greatly restricts its therapeutic effect. In this study, we aimed to develop ideal O2 self-supplementing nanoparticles for imaging-guided enhanced sonodynamic therapy of tumors with the adept coalescence of biology with nanotechnology. Methods: Based on the natural enzyme system of red blood cells (RBC), biomimetic nanoparticles (QD@P)Rs were fabricated by encapsulating Ag2S quantum dots (QD) in RBC vesicle membranes. The anti-tumor drug PEITC was employed to increase the intracellular H2O2 concentration in tumor cells. Results:In vitro and in vivo experiments demonstrated excellent biocompatibility and prolonged blood circulation of (QD@P)Rs. Following oral administration of PEITC in mice to improve the H2O2 concentration, the enzyme in the nanoprobe catalyzed endogenous H2O2 to increase O2 content and effectively alleviate tumor hypoxia. Triggered by ultrasound under the guidance of fluorescence imaging, (QD@P)Rs generated reactive oxygen species (ROS) to induce tumor cell death, and the increased content of O2 significantly enhanced the effect of SDT. Conclusion: Ag2S QDs were used, for the first time, as a sonosensitizer in the SDT field. In this study, we integrated the advantages of the natural enzyme system and SDT to develop a novel approach for effective non-invasive treatment of cancer.
Assuntos
Biomimética/métodos , Neoplasias do Colo/terapia , Membrana Eritrocítica/química , Nanopartículas/administração & dosagem , Oxigênio/metabolismo , Compostos de Prata/química , Terapia por Ultrassom/métodos , Animais , Anticarcinógenos/farmacologia , Linhagem Celular Tumoral , Neoplasias do Colo/diagnóstico por imagem , Neoplasias do Colo/metabolismo , Diagnóstico por Imagem/métodos , Modelos Animais de Doenças , Isotiocianatos/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Nanopartículas/química , Espécies Reativas de Oxigênio/metabolismoRESUMO
Nanocarrier for augmenting the efficacy of reactive oxygen species (ROS) by tumor microenvironment (TME) has become an emerging strategy for cancer treatment. Herein, a smart biodegradable drug delivery nanoplatform with mitochondrial-targeted ability, pH-responsive drug release and enzyme-like catalytic function is designed. This efficient ROS-generating platform uses ultrasound with deeper penetration capability as excitation source for combined chemotherapy and sonodynamic therapy (SDT) of tumor. In vitro experiments show that the nanoplatform can co-load Ce6 and DOX and be degraded in slight acid environment, and the DOX release rate is 63.91 ± 1.67%. In vivo experiments show that the nanoplatform has extremely biosafety and can be enriched in tumor site and excluded from body after 24 h. More significantly, after combined treatment, the tumors are eliminated and the mice still survive healthily without recurrence after 60 d. This is because not only it can achieve mitochondrial targeting and use platinum particle to increase oxygen content in TME to enhance the effect of SDT, but also it can use weak acidic TME to accelerate drug release to achieve the combination of chemotherapy and SDT. The probe provides a new strategy for designing ROS-based nanoplatform for the treatment of malignant tumor.
Assuntos
Nanopartículas , Neoplasias , Animais , Linhagem Celular Tumoral , Sistemas de Liberação de Medicamentos , Camundongos , Neoplasias/tratamento farmacológico , Espécies Reativas de Oxigênio , Microambiente TumoralRESUMO
Despite burgeoning development of nanoplatform made in the past few years, it remains a challenge to produce drug nanocarrier that enables requested on/off drug release. Thus, this study aimed to develop an ideal near-infrared light-triggered smart nanocarrier for targeted imaging-guided treatment of cancer that tactfully integrated photothermal therapy with chemotherapy to accurately control drug release time and dosage. Methods: This delivery system was composed of Ag2S QD coating with dendritic mesoporous silica (DMSN), which acted as nanocarrier of doxorubicin localized inside pores. To provide the nanocarrier with controlled release capability, a polypeptide-engineered that structure was reversible to photothermal effect of Ag2S QD, was covalently grafted to the external surface of drug-loaded DMSN. Results: This nanocarrier with the size of 40~60 nm had satisfactory biocompatibility and photothermal conversion efficiency up to 28.35%. Due to acidity-triggered charge reversal of polypeptide, which significantly extended circulation time and improved targeting ability, fluorescence and photoacoustic signals were still obvious at tumor site post-24 h by tail vein injection and chemo-photothermal synergistic therapy obviously enhanced antitumor efficacy. Mild PTT with multiple short-term exposures not only reduced the side effect of overdose drug but also avoided skin damage caused by long-term irradiation. Conclusion: By adjusting irradiation time and on/off cycle, multiple small amount local drug release reduced the side effect of overdose drug and skin damage. This novel approach provided an ideal near-infrared light-triggered nanocarrier with accurate control of area, time, and especially dosage.
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Portadores de Fármacos/química , Nanopartículas/química , Peptídeos/química , Animais , Linhagem Celular Tumoral , Terapia Combinada/métodos , Doxorrubicina/química , Sistemas de Liberação de Medicamentos/métodos , Liberação Controlada de Fármacos/efeitos dos fármacos , Fluorescência , Células HeLa , Humanos , Raios Infravermelhos , Células MCF-7 , Camundongos , Camundongos Nus , Neoplasias/tratamento farmacológico , Neoplasias/terapia , Técnicas Fotoacústicas/métodos , Fototerapia/métodos , Dióxido de Silício/químicaRESUMO
Given their superior penetration depths, photosensitizers with longer absorption wavelengths present broader application prospects in photodynamic therapy (PDT). Herein, Ag2 S quantum dots were discovered, for the first time, to be capable of killing tumor cells through the photodynamic route by near-infrared light irradiation, which means relatively less excitation of the probe compared with traditional photosensitizers absorbing short wavelengths. On modification with polydopamine (PDA), PDA-Ag2 S was obtained, which showed outstanding capacity for inducing reactive oxygen species (increased by 1.69â times). With the addition of PDA, Ag2 S had more opportunities to react with surrounding O2 , which was demonstrated by typical triplet electron spin resonance (ESR) analysis. Furthermore, the PDT effects of Ag2 S and PDA-Ag2 S achieved at longer wavelengths were almost identical to the effects produced at 660â nm, which was proved by studies in vitro. PDA-Ag2 S showed distinctly better therapeutic effects than Ag2 S in experiments in vivo, which further validated the enhanced regulatory effect of PDA. Altogether, a new photosensitizer with longer absorption wavelength was developed by using the hitherto-unexplored photodynamic function of Ag2 S quantum dots, which extended and enhanced the regulatory effect originating from PDA.
Assuntos
Indóis/uso terapêutico , Neoplasias/tratamento farmacológico , Fotoquimioterapia , Fármacos Fotossensibilizantes/uso terapêutico , Polímeros/uso terapêutico , Pontos Quânticos/uso terapêutico , Compostos de Prata/uso terapêutico , Animais , Feminino , Células HeLa , Humanos , Células MCF-7 , Camundongos Endogâmicos BALB C , Neoplasias/metabolismo , Neoplasias/patologia , Fotoquimioterapia/métodos , Pontos Quânticos/ultraestrutura , Espécies Reativas de Oxigênio/metabolismoRESUMO
Currently, a large number of anti-tumor drug delivery systems have been widely used in cancer therapy. However, due to the molecular complexity and multidrug resistance of tumors, monotherapies remain suboptimal. Thus, this study aimed to develop a multifunctional theranostic nanoplatform for effective cancer therapy. Methods: Folic acid-modified silver sulfide@mesoporous silica core-shell nanoparticle was first modified with desthiobiotin (db) on the surface, then doxorubicin (DOX) was loaded into pore. Avidin was employed as "gatekeeper" to prevent leakage of DOX via desthiobiotin-avidin interaction. Db-modified survivin antisense oligonucleotide (db-DNA) which could inhibit survivin expression was then grafted on avidin at the outer layer of nanoparticle. DOX release and db-DNA dissociation were simultaneously triggered by overexpressing biotin in cancer cells, then combining PTT from Ag2S QD to inhibit tumor growth. Results: This nanoprobe had satisfactory stability and photothermal conversion efficiency up to 33.86% which was suitable for PTT. Due to the good targeting ability and fluorescent anti-bleaching, its signal still existed at the tumor site after tail vein injection of probe into HeLa tumor-bearing nude mice for 48 h. In vitro and in vivo antitumor experiments both demonstrated that drug, gene and photothermal synergistic therapy significantly enhanced antitumor efficacy with minimal systemic toxicity. Conclusion: Our findings demonstrate that this novel nanoplatform for targeted image-guided treatment of tumor and tactfully integrated chemotherapy, photothermal therapy (PTT) and gene therapy might provide an insight for cancer theranostics.
Assuntos
Tratamento Farmacológico/métodos , Terapia Genética/métodos , Hipertermia Induzida/métodos , Terapia de Alvo Molecular/métodos , Neoplasias/diagnóstico , Neoplasias/terapia , Fototerapia/métodos , Animais , Antineoplásicos/administração & dosagem , Biotina/administração & dosagem , Biotina/análogos & derivados , Terapia Combinada/métodos , Modelos Animais de Doenças , Doxorrubicina/administração & dosagem , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos , Células HeLa , Humanos , Camundongos Nus , Nanopartículas/administração & dosagem , Nanopartículas/química , Oligonucleotídeos Antissenso/administração & dosagem , Radioterapia Guiada por Imagem/métodos , Nanomedicina Teranóstica/métodos , Resultado do TratamentoRESUMO
A graphene quantum dot (GQD) is a novel carbon nanomaterial with the advantages of low cost and no pollution. It has attracted serious attention in the biomedical fields because of its stabilities and tunable fluorescence wavelength. In this manuscript, an N-doped graphene quantum dot (N-GQD) was synthesized by a hydrothermal method using citric acid as the carbon source and urea as the nitrogen source. X-ray diffraction, Raman spectroscopy, transmission electron microscopy, UV-vis absorption spectrum, and fluorescence spectrum were used to characterize the N-GQD. The results showed that the N-GQD had a uniform size of about 5 nm. The two fluorescence emission peaks, one in the visible light region showed a 49.75% quantum yield, while another in the near infrared region was 2.49%. The photothermal conversion efficiency was 62.53%, higher than any kind of carbon nanomaterial in existence today. MTT and a long-term cytotoxicity experiment confirmed that the N-GQD had low cytotoxicity. The probe also had the ability of photoacoustic response at the same time. After coupling with folic acid, it presented imaging and photothermal therapy on the cells, which has great application prospects in the early diagnosis and treatment of tumors.
Assuntos
Grafite/química , Luz , Nitrogênio/química , Imagem Óptica/métodos , Pontos Quânticos/química , Temperatura , Células A549 , Adsorção , Ácido Fólico/química , Células HeLa , Humanos , Técnicas Fotoacústicas , Pontos Quânticos/ultraestrutura , Espectroscopia de Infravermelho com Transformada de Fourier , Análise Espectral Raman , Propriedades de Superfície , Difração de Raios XRESUMO
BACKGROUND: Ag2S has the characteristics of conventional quantum dot such as broad excitation spectrum, narrow emission spectrum, long fluorescence lifetime, strong anti-bleaching ability, and other optical properties. Moreover, since its fluorescence emission is located in the NIR-II region, has stronger penetrating ability for tissue. Ag2S quantum dot has strong absorption during the visible and NIR regions, it has good photothermal and photoacoustic response under certain wavelength excitation. RESULTS: 200 nm aqueous probe Ag2S@DSPE-PEG2000-FA (Ag2S@DP-FA) with good dispersibility and stability was prepared by coating hydrophobic Ag2S with the mixture of folic acid (FA) modified DSPE-PEG2000 (DP) and other polymers, it was found the probe had good fluorescent, photoacoustic and photothermal responses, and a low cell cytotoxicity at 50 µg/mL Ag concentration. Blood biochemical analysis, liver enzyme and tissue histopathological test showed that no significant influence was observed on blood and organs within 15 days after injection of the probe. In vivo and in vitro fluorescence and photoacoustic imaging of the probe further demonstrated that the Ag2S@DP-FA probe had good active targeting ability for tumor. In vivo and in vitro photothermal therapy experiments confirmed that the probe also had good ability of killing tumor by photothermal. CONCLUSIONS: Ag2S@DP-FA was a safe, integrated diagnosis and treatment probe with multi-mode imaging, photothermal therapy and active targeting ability, which had a great application prospect in the early diagnosis and treatment of tumor.