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BACKGROUND: During long-term antiplatelet agents (APAs) administration, patients with thrombotic diseases take a fairly high risk of life-threatening bleeding, especially when in need of urgent surgery. Rapid functional reversal of APAs remains an issue yet to be efficiently resolved by far due to the lack of any specific reversal agent in the clinic, which greatly restricts the use of APAs. METHODS: Flow cytometry analysis was first applied to assess the dose-dependent reversal activity of platelet-mimicking perfluorocarbon-based nanosponges (PLT-PFCs) toward ticagrelor. The tail bleeding time of mice treated with APAs followed by PLT-PFCs was recorded at different time points, along with corresponding pharmacokinetic analysis of ticagrelor and tirofiban. A hemorrhagic transformation model was established in experimental stroke mice with thrombolytic/antiplatelet therapy. Magnetic resonance imaging was subsequently applied to observe hemorrhage and thrombosis in vivo. Further evaluation of the spontaneous clot formation activity of PLT-PFCs was achieved by clot retraction assay in vitro. RESULTS: PLT-PFCs potently reversed the antiplatelet effect of APAs by competitively binding with APAs. PLT-PFCs showed high binding affinity comparable to fresh platelets in vitro with first-line APAs, ticagrelor and tirofiban, and efficiently reversed their function in both tail bleeding and postischemic-reperfusion models. Moreover, the deficiency of platelet intrinsic thrombotic activity diminished the risk of thrombogenesis. CONCLUSIONS: This study demonstrated the safety and effectiveness of platelet-mimicking nanosponges in ameliorating the bleeding risk of different APAs, which offers a promising strategy for the management of bleeding complications induced by antiplatelet therapy.
Assuntos
Inibidores da Agregação Plaquetária , Trombose , Animais , Camundongos , Inibidores da Agregação Plaquetária/efeitos adversos , Plaquetas , Ticagrelor/efeitos adversos , Tirofibana/efeitos adversos , Hemorragia/induzido quimicamente , Trombose/tratamento farmacológico , Trombose/prevenção & controle , Trombose/induzido quimicamenteRESUMO
Antiplatelet agents, particularly P2Y12 receptor inhibitors, are critical medicines in the prevention and treatment of thrombotic diseases in the clinic. However, their long-term use introduces a significant risk of bleeding in patients with cardiovascular diseases. Whether the bleeding is caused by the drug itself or due to surgical procedures or trauma, the need to rapidly reverse the effects of antiplatelet agents in the circulation is essential; however, no such agents are currently available. To address this need, here we describe a strategy that uses cell-membrane-wrapped nanoparticles (CM-NPs) for the rapid reversal of P2Y12 inhibitors. CM-NPs are fabricated with membranes derived from 293T cells genetically engineered to overexpress the P2Y12 receptor. Our findings support the potential of CM-NPs as a strategy for managing bleeding complications associated with P2Y12 receptor inhibitors, offering an approach to improve the safety in the use of these drugs in clinical settings.
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Acute myeloid leukemia (AML) is a fatal hematologic disease. Diagnosis and proper treatment are important for prognosis. High myeloperoxidase (MPO) expression AML cells are characterized with high levels of hypochlorite (ClO-). In this study, we report a ClO--activated theranostic agent, FNC, for AML therapy. FNC responds to ClO- specifically in high MPO expression AML cells, resulting in bright fluorescence and chlorambucil release. FNC can be used to quickly distinguish high MPO expression AML cells from other cells, including low MPO expression leukemia and activated inflammatory cells. FNC exhibits selective toxicity to highly MPO expression AML cells and can efficiently inhibit tumor growth. Meanwhile, FNC can be used to indicate differentiation through the detection of ClO-.
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The control of DNA assembly systems on cells has increasingly shown great importance for precisely targeted therapies. Here, we report a controllable DNA self-assembly system based on the regulation of G-quadruplex DNA topology by a reduction-sensitive azobenzene ligand. Specifically, three azobenzene multiamines are developed, and AzoDiTren is identified as the best G4 binder, which displays high affinity and specificity for G4 DNA. Moreover, the reduction-sensitive nature of the azobenzene scaffold allows AzoDiTren to induce a complete change of the G4 topology in a tissue-specific manner, even at high metal cation concentrations. On this basis, the AzoDiTren-induced G4 conformational switch achieves control of the self-assembly of G4-functionalized DNAs on cells. This strategy enables the regulation of G4 and DNA self-assembly by the bioreductant-responsive ligand.
Assuntos
Quadruplex G , Ligantes , DNA , Compostos Azo/farmacologiaRESUMO
A major challenge in cancer vaccine therapy is the efficient delivery of antigens and adjuvants to stimulate a controlled yet robust tumour-specific T-cell response. Here, we describe a structurally well defined DNA nanodevice vaccine generated by precisely assembling two types of molecular adjuvants and an antigen peptide within the inner cavity of a tubular DNA nanostructure that can be activated in the subcellular environment to trigger T-cell activation and cancer cytotoxicity. The integration of low pH-responsive DNA 'locking strands' outside the nanostructures enables the opening of the vaccine in lysosomes in antigen-presenting cells, exposing adjuvants and antigens to activate a strong immune response. The DNA nanodevice vaccine elicited a potent antigen-specific T-cell response, with subsequent tumour regression in mouse cancer models. Nanodevice vaccination generated long-term T-cell responses that potently protected the mice against tumour rechallenge.
Assuntos
Vacinas Anticâncer/imunologia , Melanoma Experimental/terapia , Vacinas de DNA/genética , Vacinas de DNA/imunologia , Adjuvantes Imunológicos/administração & dosagem , Animais , Apresentação de Antígeno , Bacteriófago M13/genética , Vacinas Anticâncer/administração & dosagem , Vacinas Anticâncer/genética , Testes Imunológicos de Citotoxicidade , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Concentração de Íons de Hidrogênio , Imunoterapia/métodos , Metástase Linfática/prevenção & controle , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Linfócitos do Interstício Tumoral/imunologia , Melanoma Experimental/imunologia , Melanoma Experimental/patologia , Camundongos Endogâmicos C57BL , Vacinas de DNA/administração & dosagemRESUMO
The booming growth of all inorganic cesium lead halide perovskites in optoelectronic applications has prompted extensive research interest in the fabrication of ordered nanostructures or microarrays for enhanced device performances. However, the high cost and complexity of commercial lithographic approaches impede the facile fabrication of perovskite microarrays. Herein, CsPbBr3 microarrays with tunable periodicities have been fabricated using a self-assembled polystyrene nanosphere template and a co-evaporation method. The periodicity of CsPbBr3 microarrays is precisely manipulated by simply modifying the size of polystyrene nanospheres. These microarrays are beneficial for light harvesting, leading to better light absorption ability and prolonged photoinduced carrier lifetime. The longest average carrier lifetime of 58.3 ns is obtained for CsPbBr3 microarrays with a periodicity of 1.0 µm. More importantly, the periodic structures of CsPbBr3 microarrays result in a tunable density of emitter tips in field emission devices. Compared to compact CsPbBr3 films, a 68.2% decrease of the turn-on field is observed for CsPbBr3 microarrays when the periodicity is 150 nm. The higher density of emitter tips leads to larger local field enhancement, and hence the largest field enhancement factor of 3346.6. Finally, a good emission current stability for CsPbBr3 microarray-based field emission devices has been demonstrated.
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Compared with traditional chemotherapeutics, vascular disruption agents (VDAs) have the advantages of rapidly blocking the supply of nutrients and starving tumors to death. Although the VDAs are effective under certain scenarios, this treatment triggers angiogenesis in the later stage of therapy that frequently leads to tumor recurrence and treatment failure. Additionally, the nonspecific tumor targeting and considerable side effects also impede the clinical applications of VDAs. Here we develop a customized strategy that combines a VDA with an anti-angiogenic drug (AAD) using mesoporous silica nanoparticles (MSNs) coated with platelet membrane for the self-assembled tumor targeting accumulation. The tailor-made nanoparticles accumulate in tumor tissues through the targeted adhesion of platelet membrane surface to damaged vessel sites, resulting in significant vascular disruption and efficient anti-angiogenesis in animal models. This study demonstrates the promising potential of combining VDA and AAD in a single nanoplatform for tumor eradication.
Assuntos
Nanopartículas , Neoplasias , Inibidores da Angiogênese/uso terapêutico , Animais , Neoplasias/tratamento farmacológico , Neovascularização Patológica/tratamento farmacológico , Dióxido de Silício/uso terapêuticoRESUMO
BACKGROUND The discovery of browning in white adipose tissue has provided new ideas for treating obesity. Many studies have reported that ginsenoside Rb1 (G-Rb1) has activity against diabetes, inflammation, and obesity, but further investigation is needed on the effect and mechanism of G-Rb1 on browning. MATERIAL AND METHODS We treated 3T3-L1 adipocytes with 0-200 µM G-Rb1, and 0.5 µM Compound 3f and 30 µM SKL2001 were used to activate Wnt/b-catenin signaling. Adipocyte activity was evaluated by Cell Counting Kit-8. Oil Red O staining was used to detect the lipid droplets. Quantitative real-time polymerase chain reaction was used to measure the expression of Cd-137, Cited-1, Txb-1, Prdm-16, and Ucp-1 mRNA. Western blotting was used to measure the expression of Ucp-1, pGSK-3ß (Ser 9), GSK- 3ß, and ß-catenin proteins. The expression of Ucp-1 was also detected with immunofluorescence. RESULTS Adipocyte activity was not affected by 0-100 µM G-Rb1. However, G-Rb1 dose-dependently reduced the accumulation of lipid droplets; increased the expression of Cd-137, Cited-1, Txb-1, Prdm-16, and Ucp-1 mRNA; and increased the expression of Ucp-1, pGSK-3ß (Ser 9), GSK-3ß, and ß-catenin proteins. The accumulation of lipid droplets and the expression of Ucp-1 protein decreased as b-catenin increased. CONCLUSIONS G-Rb1 at various concentrations (0-100 µM) promoted the browning of adipocytes in a dose-dependent manner. Further, we confirmed that activation of Wnt/ß-catenin signaling could inhibit browning. Therefore, the browning promoted by G-Rb1 may be associated with the inhibition of Wnt/ß-catenin signaling.
Assuntos
Adipócitos Brancos/efeitos dos fármacos , Ginsenosídeos/farmacologia , Células 3T3-L1 , Adipócitos/efeitos dos fármacos , Adipócitos Brancos/metabolismo , Adipogenia/efeitos dos fármacos , Tecido Adiposo Branco/metabolismo , Animais , Diferenciação Celular/efeitos dos fármacos , Ginsenosídeos/metabolismo , Metabolismo dos Lipídeos/fisiologia , Lipídeos/fisiologia , Camundongos , Obesidade/metabolismo , Fatores de Transcrição/metabolismo , Via de Sinalização Wnt/efeitos dos fármacos , beta Catenina/efeitos dos fármacos , beta Catenina/metabolismoRESUMO
To better make nanomedicine entering the clinic, developing new rationally designed nanotherapeutics with a deeper understanding of tumor biology is required. The tumor microenvironment is similar to the inflammatory response in a healing wound, the milieu of which promotes tumor cell invasion and metastasis. Successful targeting of the microenvironmental components with effective nanotherapeutics to modulate the tumor microvessels or restore the homeostatic mechanisms in the tumor stroma will offer new hope for cancer treatment. We here highlight the progress in constructing nanotherapeutics to target or modulate the tumor microenvironment. We discuss the factors necessary for nanomedicines to become a new paradigm in cancer therapy, including the selection of drugs and therapeutic targets, controllable synthesis, and tempo-spatial drug release.
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Nanomedicina/métodos , Nanopartículas/química , Neoplasias/tratamento farmacológico , Microambiente Tumoral/efeitos dos fármacos , Animais , Antineoplásicos/farmacologia , DNA/química , Sistemas de Liberação de Medicamentos , Matriz Extracelular/metabolismo , Homeostase , Humanos , Oncologia/métodos , Oncologia/tendências , Camundongos , Nanomedicina/tendências , Invasividade Neoplásica , Metástase Neoplásica , Neovascularização Patológica , Permeabilidade , Células Estromais/metabolismoRESUMO
In recent years, tumor microenvironment (TME) has been recognized as potential targets for tumor treatment and the tumor vascular system is one of such targets. Fusing truncated tissue factor (tTF) with pH low insertion peptides (pHLIP), tTF-pHLIP, can target tumor vessels owing to its acidic TME and cause tumor vessel occlusion by blood clotting and subsequently effectively inhibit tumor growth. To evaluate its bioeffects, we exposed the tTF-pHLIP to normal mice and mice xenograft with B16F10 tumor and analyzed the metabolic profiling of various tissues and biofluids including plasma and urine from mice treated with and without tTF-pHLIP. A combination of nuclear magnetic resonance (NMR) and gas chromatography-mass spectrometry and ultra-high-performance liquid chromatography-mass spectrometry was employed in the study. We found that tTF-pHLIP treatment can effectively reduce tumor size and concurrently ameliorate tumor-induced alterations in the TCA cycle metabolism and lipid metabolism. In addition, we found that toxicity of tTF-pHLIP to normal mice is minor and exposure of the tTF-pHLIP induced oxidative stress to the system. Hence, we concluded that tTF-pHLIP is of low toxicity and effective in reducing tumor size as well as rebalancing tumor-induced metabolic derailment.
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Melanoma Experimental/irrigação sanguínea , Melanoma Experimental/tratamento farmacológico , Proteínas de Membrana/genética , Metaboloma/efeitos dos fármacos , Proteínas Recombinantes de Fusão/farmacologia , Animais , Ácidos Graxos/análise , Ácidos Graxos/metabolismo , Feminino , Espectroscopia de Ressonância Magnética , Melanoma Experimental/patologia , Camundongos Endogâmicos C57BL , Proteínas Recombinantes de Fusão/genética , Tromboplastina/genética , Carga Tumoral , Microambiente TumoralRESUMO
The limited efficacy of single-agent immune checkpoint inhibitors in treating tumors has prompted investigations on their combination partners. Here, a tumor-homing indoleamine 2,3-dioxygenase (IDO) nanoinhibitor is reported to selectively inhibit immunosuppressive IDO pathway in the tumor microenvironment. It is self-assembled from a modularly designed peptide-drug conjugate containing a hydrophilic targeting motif (arginyl-glycyl-aspartic acid; RGD), two protonatable histidines, and an ester bond-linked hydrophobic IDO inhibitor, which exhibits pH-responsive disassembly and esterase-catalyzed drug release. Markedly, it achieved potent and persistent inhibition of intratumoral IDO activity with a reduced systemic toxicity, which greatly enhanced the therapeutic efficacy of programmed cell death-ligand 1 blockade in vivo. Overall, this study provides a promising paradigm of combinatorial normalization immunotherapy by exploiting a targeted IDO nanoinhibitor to augment the antitumor immunity of checkpoint inhibitors.
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Antígeno B7-H1/antagonistas & inibidores , Desenho de Fármacos , Indolamina-Pirrol 2,3,-Dioxigenase/antagonistas & inibidores , Nanopartículas , Pró-Fármacos/farmacologia , Humanos , Imunoterapia , Oligopeptídeos/química , Pró-Fármacos/farmacocinética , Microambiente TumoralRESUMO
Nucleic acid therapy is and will continue to be of great interest in cancer treatment. The development of nanocarriers with high nucleic acid loading capacity, low toxicity, and specific targeting, with excellent pharmacokinetic/pharmacodynamic profiles, will enable us to realize safe and effective nucleic acid therapy. Tremendous efforts have been directed toward the production of optimized theranostic nanocarriers that can simultaneously provide treatment and real-time monitoring to aid researchers and physicians in making adaptation strategies during early drug development and patient's treatment, respectively. In this review, several nanomaterials with inherent optical and magnetic properties, developed for bioimaging and imaging-guided nucleic acid therapies, are introduced and discussed. In each subsection, the unique characteristics of the corresponding theranostic nanomaterials are reviewed and discussed with examples. Finally, we present the remaining challenges that must be addressed and provide our opinions on the future of nanomaterial medicines for bioimaging and imaging-guided nucleic acid therapy.
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Fenômenos Magnéticos , Imagem Molecular/métodos , Nanomedicina/métodos , Ácidos Nucleicos/uso terapêutico , Fenômenos Ópticos , Animais , Humanos , Neoplasias/diagnóstico por imagem , Neoplasias/terapia , Ácidos Nucleicos/químicaRESUMO
BACKGROUND: Spartina alterniflora is an invasive plant on the coast of China that replaces native vegetation and has a serious negative impact on local ecosystems. Monitoring the spatial distribution of S. alterniflora and its changes over time can reveal its expansion mechanism, which is crucial for the management of coastal ecosystems. The purpose of this study was to map the distribution of S. alterniflora in Zhejiang Province from 1985 to 2015 using a time series of Landsat TM/OLI images and analyze the temporal and spatial patterns of expansion of this species. RESULTS: After analyzing the distribution of coastal vegetation, the vegetation index was calculated based on Landsat images for 4 years (1985, 1995, 2005 and 2015). According to a threshold determined based on expert knowledge, the distribution of S. alterniflora in Zhejiang Province was extracted, and the temporal and spatial changes in the distribution of S. alterniflora were analyzed. The classification accuracy was 90.3%. S. alterniflora has expanded rapidly in recent decades after being introduced into southern Zhejiang. Between 1985 and 2015, S. alterniflora increased its area of distribution by 10,000 hm2, and it replaced native vegetation to become the most abundant halophyte in tidal flats. Overall, S. alterniflora expanded from south to north over the decades of the study, and the fastest expansion rate was 463.64 hm2/year, which occurred between 1995 and 2005. S. alterniflora was widely distributed in the tidal flats of bays and estuaries and expanded outward as sediment accumulated. CONCLUSIONS: This study reveals the changes over time in S. alterniflora cover in Zhejiang and can contribute to the control and management of this invasive plant.
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Ecossistema , Áreas Alagadas , China , Espécies Introduzidas , PoaceaeRESUMO
Within tumors, the coagulation-inducing protein tissue factor (TF), a major initiator of blood coagulation, has been shown to play a critical role in the hematogenous metastasis of tumors, due to its effects on tumor hypercoagulability and on the mediation of interactions between platelets and tumor cells. Targeting tumor-associated TF has therefore great therapeutic potential for antimetastasis therapy and preventing thrombotic complication in cancer patients. Herein, we reported a novel peptide-based nanoparticle that targets delivery and release of small interfering RNA (siRNA) into the tumor site to silence the expression of tumor-associated TF. We showed that suppression of TF expression in tumor cells blocks platelet adhesion surrounding tumor cells in vitro. The downregulation of TF expression in intravenously administered tumor cells (i.e., simulated circulating tumor cells [CTCs]) prevented platelet adhesion around CTCs and decreased CTCs survival in the lung. In a breast cancer mouse model, siRNA-containing nanoparticles efficiently attenuated TF expression in the tumor microenvironment and remarkably reduced the amount of lung metastases in both an experimental lung metastasis model and tumor-bearing mice. What's more, this strategy reversed the hypercoagulable state of the tumor bearing mice by decreasing the generation of thrombin-antithrombin complexes (TAT) and activated platelets, both of which are downstream products of TF. Our study describes a promising approach to combat metastasis and prevent cancer-associated thrombosis, which advances TF as a therapeutic target toward clinic applications.
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Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Inativação Gênica , Neoplasias Pulmonares , Nanopartículas , Proteínas de Neoplasias , Neoplasias Experimentais , RNA Interferente Pequeno , Trombofilia , Tromboplastina , Trombose , Animais , Linhagem Celular Tumoral , Feminino , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/secundário , Camundongos Nus , Nanopartículas/química , Nanopartículas/uso terapêutico , Metástase Neoplásica , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/genética , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/genética , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Células Neoplásicas Circulantes/metabolismo , Células Neoplásicas Circulantes/patologia , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/farmacologia , Trombofilia/genética , Trombofilia/metabolismo , Trombofilia/prevenção & controle , Tromboplastina/biossíntese , Tromboplastina/genética , Trombose/genética , Trombose/metabolismo , Trombose/patologia , Trombose/prevenção & controleRESUMO
Activated platelets have a high affinity for tumor cells, and consequently, they can protect tumor cells from environmental stress and immune attacks. Therefore, preventing platelet-tumor cell interaction can lead to the elimination of circulating tumor cells via natural killer cells and finally metastasis inhibition. It is also shown that CREKA (Cys-Arg-Glu-Lys-Ala), a tumor-homing pentapeptide, targets fibrin-fibronectin complexes that are found on the tumor stroma and the vessel walls. In this study, we linked CREKA to Ticagrelor, a reversible antagonist of the P2Y12 receptor on platelets. In vitro experiments indicated that CREKA-Ticagrelor could not only inhibit the platelet-induced migration of tumor cells with an invasive phenotype but also prevent tumor-platelet interaction. In vivo antitumor and antimetastasis results of this drug showed that CREKA-Ticagrelor could specifically target the tumor tissues within 24 h post intravenous injection and suppress lung metastasis. Meanwhile, by having this antiplatelet drug targeted, its side effects were minimized, and bleeding risk was decreased. Thus, CREKA-Ticagrelor offers an efficient antimetastatic agent.
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Peptídeo Hidrolases/química , Peptídeo Hidrolases/farmacologia , Inibidores da Agregação Plaquetária/química , Inibidores da Agregação Plaquetária/farmacologia , Ticagrelor/química , Animais , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Metástase Neoplásica/prevenção & controle , Peptídeo Hidrolases/efeitos adversos , Peptídeo Hidrolases/farmacocinética , Agregação Plaquetária/efeitos dos fármacos , Inibidores da Agregação Plaquetária/efeitos adversos , Inibidores da Agregação Plaquetária/farmacocinética , Segurança , Distribuição Tecidual , Cicatrização/efeitos dos fármacosRESUMO
Combination therapeutic regimen is becoming a primary direction for current cancer immunotherapy to broad the antitumor response. Functional nanomaterials offer great potential for steady codelivery of various drugs, especially small molecules, therapeutic peptides, and nucleic acids, thereby realizing controllable drug release, increase of drug bioavailability, and reduction of adverse effects. Herein, a therapeutic peptide assembling nanoparticle that can sequentially respond to dual stimuli in the tumor extracellular matrix was designed for tumor-targeted delivery and on-demand release of a short d-peptide antagonist of programmed cell death-ligand 1 (DPPA-1) and an inhibitor of idoleamine 2,3-dioxygenase (NLG919). By concurrent blockade of immune checkpoints and tryptophan metabolism, the nanoformulation increased the level of tumor-infiltrated cytotoxic T cells and in turn effectively inhibited melanoma growth. To achieve this, an amphiphilic peptide, consisting of a functional 3-diethylaminopropyl isothiocyanate (DEAP) molecule, a peptide substrate of matrix metalloproteinase-2 (MMP-2), and DPPA-1, was synthesized and coassembled with NLG919. The nanostructure swelled when it encountered the weakly acidic tumor niche where DEAP molecules were protonated, and further collapsed due to the cleavage of the peptide substrate by MMP-2 that is highly expressed in tumor stroma. The localized release of DPPA-1 and NLG919 created an environment which favored the survival and activation of cytotoxic T lymphocytes, leading to the slowdown of melanoma growth and increase of overall survival. Together, this study offers new opportunities for dual-targeted cancer immunotherapy through functional peptide assembling nanoparticles with design features that are sequentially responsive to the multiple hallmarks of the tumor microenvironment.
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Preparações de Ação Retardada/química , Imidazóis/administração & dosagem , Isoindóis/administração & dosagem , Melanoma/terapia , Nanopartículas/química , Peptídeos/administração & dosagem , Animais , Antígeno B7-H1/antagonistas & inibidores , Sistemas de Liberação de Medicamentos , Imidazóis/uso terapêutico , Imunoterapia , Isoindóis/uso terapêutico , Camundongos , Camundongos Nus , Peptídeos/uso terapêutico , Microambiente Tumoral/efeitos dos fármacosRESUMO
The targeted delivery of hydrophobic therapeutic drugs to tumors is one of the major challenges in drug development. The use of natural proteins as drug delivery vehicles holds great promise due to various functionalities of proteins. In the current study, we exploited a natural protein, GroEL, which possesses a double layer cage structure, as a hydrophobic drug container, which is switchable by ATP binding to a hydrophilic status, to design a novel and intelligent hydrophobic drug delivery molecular machine with a controlled drug release profile. When loaded with the hydrophobic antitumor drug, Doxorubicin (Dox), GroEL was able to shield the drug from the aqueous phase of blood, releasing the drug once in the presence of a critical concentration of ATP at the tumor site. Unexpectedly, we found that GroEL has a specific affinity for the cell structural protein, plectin, which is expressed at abnormally elevated levels on the membranes of tumor cells but not in normal cells. This finding, in combination with the ATP sensitivity, makes GroEL a superior natural tumor targeting nanocarrier. Our data show that GroEL-Dox is able to effectively, and highly selectively, deliver the hydrophobic drug to fast growing tumors without overt adverse effects on the major organs. GroEL is therefore a promising drug delivery platform that can overcome the obstacles to hydrophobic drug targeting and delivery.
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Antibióticos Antineoplásicos/administração & dosagem , Chaperonina 60/metabolismo , Preparações de Ação Retardada/metabolismo , Doxorrubicina/administração & dosagem , Sistemas de Liberação de Medicamentos , Neoplasias Pancreáticas/tratamento farmacológico , Trifosfato de Adenosina/metabolismo , Animais , Antibióticos Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Doxorrubicina/uso terapêutico , Humanos , Interações Hidrofóbicas e Hidrofílicas , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias Pancreáticas/patologia , Plectina/metabolismoRESUMO
Polycyclic aromatic hydrocarbons (PAHs) are of concern for both ecosystem and human health due to their potential teratogenic, carcinogenic, and mutagenic properties. The concentration of ∑16PAHs in foliar dust ranged from 49.4 to 19,018.1 µg kg-1, with a mean value of 7074.5 µg kg-1. There were significant seasonal variations in the concentration of ∑16PAHs, with the concentration in winter being almost twice as high as in summer. Similarly, the differences between PAH profiles in different seasons indicated that they had common sources, which were attributed to the combined effect of regional transport and local emissions. The diagnostic ratios of indicator compounds indicated that PAHs detected in foliar dust originated from a mixture of gasoline vehicle emissions, biomass, and coal combustion in Nanjing. According to the ecological risk classification of ∑16PAHs, the ecological risk caused by PAHs was high since the value of RQ∑16PAHs(MPCs) was ≥ 1 and RQ∑16PAHs(NCs) were ≥ 800. The mean values for RQ∑16PAHs(MPCs) and RQ∑16PAHs(NCs) were 14.8 and 2368.9, which indicated a relatively high ecological risks of PAHs in foliar dust in Nanjing.
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Carvão Mineral/análise , Poeira/análise , Monitoramento Ambiental/métodos , Hidrocarbonetos Policíclicos Aromáticos/análise , Emissões de Veículos/análise , China , Ecossistema , Humanos , Medição de Risco , Estações do AnoRESUMO
Tumor-associated macrophages (TAM) play pivotal roles in cancer initiation and progression. Monocytes, the precursors of TAMs, normally undergo spontaneous apoptosis within 2 days, but can subsist in the inflammatory tumor microenvironment for continuous survival and generation of sufficient TAMs. The mechanisms underlying tumor-driving monocyte survival remain obscure. Here we report that cancer cell-derived exosomes were crucial mediators for monocyte survival in the inflammatory niche. Analysis of the survival-promoting molecules in monocytes revealed that cancer cell-derived exosomes activated Ras and extracellular signal-regulated kinases in the mitogen-activated protein kinase (MAPK) pathway, resulting in the prevention of caspase cleavage. Phosphorylated receptor tyrosine kinases (RTKs), such as phosphorylated epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER-2), were abundantly expressed in cancer cell-derived exosomes. Knock-out of EGFR or/and HER-2, or alternatively, inhibitors against their phosphorylation significantly disturbed the exosome-mediated activation of the MAPK pathway, inhibition of caspase cleavage, and increase in survival rate in monocytes. Moreover, the deprived survival-stimulating activity of exosomes due to null expression of EGFR and HER-2 could be restored by activation of another RTK, insulin receptor. Overall, our study uncovered a mechanism of tumor-associated monocyte survival and demonstrated that cancer cell-derived exosomes can stimulate the MAPK pathway in monocytes through transport of functional RTKs, leading to inactivation of apoptosis-related caspases. This work provides insights into the long sought question on monocyte survival prior to formation of plentiful TAMs in the tumor microenvironment.