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1.
Nat Commun ; 12(1): 5733, 2021 09 30.
Artigo em Inglês | MEDLINE | ID: mdl-34593794

RESUMO

In addition to increasing the expression of programmed death-ligand 1 (PD-L1), tumor cells can also secrete exosomal PD-L1 to suppress T cell activity. Emerging evidence has revealed that exosomal PD-L1 resists immune checkpoint blockade, and may contribute to resistance to therapy. In this scenario, suppressing the secretion of tumor-derived exosomes may aid therapy. Here, we develop an assembly of exosome inhibitor (GW4869) and ferroptosis inducer (Fe3+) via amphiphilic hyaluronic acid. Cooperation between the two active components in the constructed nanounit induces an anti-tumor immunoresponse to B16F10 melanoma cells and stimulates cytotoxic T lymphocytes and immunological memory. The nanounit enhances the response to PD-L1 checkpoint blockade and may represent a therapeutic strategy for enhancing the response to this therapy.

2.
Chem Commun (Camb) ; 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34652356

RESUMO

Photothermal therapy (PTT) achieves substantive therapeutic progress in certain tumor types without exogenous agents but is hampered by the over-activated inflammatory response or tumor recurrence in some cases. Herein, we technically developed the metal-polyphenolic nanosystem with precise NIR-II fluorescence-imaging guidance for combining hafnium (Hf)-sensitized radiotherapy with PTT to regress tumor growth.

3.
J Nanobiotechnology ; 19(1): 275, 2021 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-34503490

RESUMO

BACKGROUND: Skin injury and the resultant defects are common clinical problems, and usually lead to chronic skin ulcers and even life-threatening diseases. Copper, an essential trace element of human body, has been reported to promote the regeneration of skin by stimulating proliferation of endothelial cell and enhance angiogenesis. RESULTS: Herein, we have prepared a new donut-like metal-organic frameworks (MOF) of copper-nicotinic acid (CuNA) by a simple solvothermal reaction. The rough surface of CuNA is beneficial for loading/release basic fibroblast growth factor (bFGF). The CuNAs with/without bFGF are easily processed into a light-responsive composite hydrogel with GelMA, which not only show excellent mechanical properties, but also display superior biocompatibility, antibacterial ability and bioactivity. Moreover, in the in vivo full-thickness defect model of skin wound, the resultant CuNA-bFGF@GelMA hydrogels significantly accelerate the wound healing, by simultaneously inhibiting the inflammatory response, promoting the new blood vessels formation and the deposition of collagen and elastic fibers. CONCLUSIONS: Considering the superior biocompatibility, antibacterial ability and bioactivity, the CuNA and its composite light-responsive hydrogel system will be promising in the applications of skin and even other tissue regeneration.

4.
Small ; : e2102624, 2021 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-34378338

RESUMO

Targeting B7-H3 chimeric antigen receptor (CAR) T cells has antitumor potential for therapy of non-small cell lung cancer (NSCLC) in preclinical studies. However, CAR T cell therapy remains a formidable challenge for the treatment of solid tumors due to the heterogeneous and immunosuppressive tumor microenvironment (TME). Nanozymes exhibit merits modulating the immunosuppression of the tumor milieu. Here, a synergetic strategy by combination of nanozymes and CAR T cells in solid tumors is described. This nanozyme with dual photothermal-nanocatalytic properties is endowed to remodel TME by destroying its compact structure. It is found that the B7-H3 CAR T cells infused in mice engrafted with the NSCLC cells have superior antitumor activity after nanozyme ablation of the tumor. Importantly, it is found that the changes altered immune-hostile cancer environment, resulting in enhanced activation and infiltration of B7-H3 CAR T cells. The first evidence that the process of combination nanozyme therapy effectively improves the therapeutic index of CAR T cells is presented. Thus, this study clearly supports that the TME-immunomodulated nanozyme is a promising tool to improve the therapeutic obstacles of CAR T cells against solid tumors.

5.
Int J Nanomedicine ; 16: 4559-4577, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34267513

RESUMO

Purpose: Reactive oxygen species (ROS) are a group of signaling biomolecules that play important roles in the cell cycle. When intracellular ROS homeostasis is disrupted, it can induce cellular necrosis and apoptosis. It is desirable to effectively cascade-amplifying ROS generation and weaken antioxidant defense for disrupting ROS homeostasis in tumor microenvironment (TME), which has been recognized as a novel and ideal antitumor strategy. Multifunctional nanozymes are highly promising agents for ROS-mediated therapy. Methods: This study constructed a novel theranostic nanoagent based on PEG@Cu2-xS@Ce6 nanozymes (PCCNs) through a facile one-step hydrothermal method. We systematically investigated the photodynamic therapy (PDT)/photothermal therapy (PTT) properties, catalytic therapy (CTT) and glutathione (GSH) depletion activities of PCCNs, antitumor efficacy induced by PCCNs in vitro and in vivo. Results: PCCNs generate singlet oxygen (1O2) with laser (660 nm) irradiation and use catalytic reactions to produce hydroxyl radical (•OH). Moreover, PCCNs show the high photothermal performance under NIR II 1064-nm laser irradiation, which can enhance CTT/PDT efficiencies to increase ROS generation. The properties of O2 evolution and GSH consumption of PCCNs achieve hypoxia-relieved PDT and destroy cellular antioxidant defense system respectively. The excellent antitumor efficacy in 4T1 tumor-bearing mice of PCCNs is achieved through disrupting ROS homeostasis-involved therapy under the guidance of photothermal/photoacoustic imaging. Conclusion: Our study provides a proof of concept of "all-in-one" nanozymes to eliminate tumors via disrupting ROS homeostasis.


Assuntos
Homeostase/efeitos dos fármacos , Hipertermia Induzida/métodos , Raios Infravermelhos , Nanomedicina/métodos , Fotoquimioterapia/métodos , Espécies Reativas de Oxigênio/metabolismo , Microambiente Tumoral/efeitos dos fármacos , Animais , Catálise , Linhagem Celular Tumoral , Cério/química , Cobre/química , Glutationa/metabolismo , Humanos , Camundongos , Polietilenoglicóis/química , Sulfetos/química
6.
Small ; : e2100314, 2021 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-34018690

RESUMO

Nanomedicine integrates different functional materials to realize the customization of carriers, aiming at increasing the cancer therapeutic efficacy and reducing the off-target toxicity. However, efforts on developing new drug carriers that combine precise diagnosis and accurate treatment have met challenges of uneasy synthesis, poor stability, difficult metabolism, and high cytotoxicity. Metal-phenolic networks (MPNs), making use of the coordination between phenolic ligands and metal ions, have emerged as promising candidates for nanomedicine, most notably through the service as multifunctional theranostic nanoplatforms. MPNs present unique properties, such as rapid preparation, negligible cytotoxicity, and pH responsiveness. Additionally, MPNs can be further modified and functionalized to meet specific application requirements. Here, the classification of polyphenols is first summarized, followed by the introduction of the properties and preparation strategies of MPNs. Then, their recent advances in biomedical sciences including bioimaging and anti-tumor therapies are highlighted. Finally, the main limitations, challenges, and outlooks regarding MPNs are raised and discussed.

7.
Adv Mater ; 33(22): e2007356, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33876449

RESUMO

Polyphenols, the phenolic hydroxyl group-containing organic molecules, are widely found in natural plants and have shown beneficial effects on human health. Recently, polyphenol-containing nanoparticles have attracted extensive research attention due to their antioxidation property, anticancer activity, and universal adherent affinity, and thus have shown great promise in the preparation, stabilization, and modification of multifunctional nanoassemblies for bioimaging, therapeutic delivery, and other biomedical applications. Additionally, the metal-polyphenol networks, formed by the coordination interactions between polyphenols and metal ions, have been used to prepare an important class of polyphenol-containing nanoparticles for surface modification, bioimaging, drug delivery, and disease treatments. By focusing on the interactions between polyphenols and different materials (e.g., metal ions, inorganic materials, polymers, proteins, and nucleic acids), a comprehensive review on the synthesis and properties of the polyphenol-containing nanoparticles is provided. Moreover, the remarkable versatility of polyphenol-containing nanoparticles in different biomedical applications, including biodetection, multimodal bioimaging, protein and gene delivery, bone repair, antibiosis, and cancer theranostics is also demonstrated. Finally, the challenges faced by future research regarding the polyphenol-containing nanoparticles are discussed.

8.
Adv Mater ; 33(22): e2008481, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33899283

RESUMO

Photothermal therapy (PTT), one of the most-potent cancer therapeutic strategies known, is highlighted with excessive inflammatory response, while ablating cancer with immunogenic death. This hyperactive immune response may override PTT-triggered immunogenicity, exacerbate skin empyrosis, and incur permanent tissue injury and high-profile tumor regeneration. Therefore, an anticancer balance between pathological and protective immune response is urgently needed for an advanced photothermal therapeutic tactic. Herein, a gas-modulated photothermal immunogenicity strategy is proposed by integrating an amphiphilic-conjugated polymer with a polysulfide-based hydrogen sulfide (H2 S) donor (2,2'-dipyridyl tetrasulfide@CP-PEG) (where CP = conjugated polymer and PEG = poly(ethylene glycol)). The CP is endowed with NIR-II fluorescence capacity and favorable photothermal effect, tracing the tumor for precise therapeutics. The polysulfide donor can release H2 S triggered by intracellular glutathione, which elicits mitochondrial dysfunction and robust anti-inflammation effect. Ultimately, this gas-modulated PTT strategy inhibits tumor growth remarkably and limits the magnitude of PTT-induced proinflammatory tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and interleukin-1beta (IL-1ß) cytokines. Moreover, the regulated inflammation accelerates PTT-induced wound healing. A H2 S-modulated PTT with adaptive immune response is thus recommended as an advanced strategy to cancer therapeutics.

9.
Biomaterials ; 269: 120638, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33421711

RESUMO

A critical challenge remains in PD-1 checkpoint blockade immunotherapy is few tumor specific T cells infiltration in hypoxic tumor microenvironment (TME). Improving immunogenic cell death (ICD) associated immunogenicity can make tumor sensitive to PD-1 checkpoint blockade immunotherapy. Herein, a phenolic ICD inducer was engineered by self-assembly of the superior ICD inducer (doxorubicin, DOX), phenolic manganese dioxide nanoreactor, ferric iron and PEG-polyphenols (MDP NPs) via metal phenolic coordination. These oxygen self-supporting MDP NPs strengthen DOX based ROS-dependent cell death and their metal mediated chemodynamic effect accelerate ICD induction. Together with concomitant ICD triggered by DOX, MDP NPs successively lead to tumor-associated antigen boosting, DCs maturation and ultimately enhance tumor-specific T cells infiltration. Furthermore, MDP NPs efficiently modulated hypoxic TME for effective macrophages recruitment. This promising ICD-augment strategy efficiently improve tumor response to PD-1 checkpoint blockade immunotherapy, resulting in a significant antitumor immune response in primary tumor and a strong abscopal effect to distant tumor. Our simple and versatile phenolic inducer expands the application of chemodrugs based ICD enhancing PD-1 checkpoint blockade immunotherapy.


Assuntos
Morte Celular Imunogênica , Imunoterapia , Neoplasias , Doxorrubicina , Humanos , Inibidores de Checkpoint Imunológico , Nanopartículas , Neoplasias/tratamento farmacológico , Polifenóis , Receptor de Morte Celular Programada 1 , Microambiente Tumoral
10.
Angew Chem Int Ed Engl ; 60(4): 1967-1975, 2021 01 25.
Artigo em Inglês | MEDLINE | ID: mdl-33078525

RESUMO

Engineering multifunctional nanoplatforms with high therapeutic benefits has become a promising strategy for intractable cancer treatment. A novel polyphenol-based nanocomplex was designed to evoke highly efficacious cancer immunosurveillance while localizing therapy on the primary tumor and to minimize systemic side effects. This nanocomplex is prepared via metal-polyphenol coordination by encapsulating a natural polyphenol, gossypol, and a newly synthesized polyphenol derivative, polyethylene glycol-Chlorin e6 (Ce6). The combination of gossypol from cotton and the photosensitizer Ce6 can induce chemotherapeutic/photodynamic immunogenic cancer cell death upon laser irradiation, which is supported by a rich maturation of dendritic cells, concentrated secretion of inflammatory cytokines, and significant inhibition of distant untreated tumors. Finally, an assistance of the programmed-cell-death ligand-1 checkpoint-blockade immunotherapy can enhance the anti-tumor immune stimulation of our nanoplatform to a higher level.


Assuntos
Nanomedicina , Neoplasias/terapia , Polifenóis/química , Antineoplásicos/uso terapêutico , Antígeno B7-H1/imunologia , Morte Celular/efeitos dos fármacos , Terapia Combinada , Humanos , Imunoterapia , Nanopartículas/uso terapêutico , Neoplasias/imunologia , Neoplasias/patologia , Fármacos Fotossensibilizantes/uso terapêutico
11.
Adv Sci (Weinh) ; 7(23): 2001914, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33304752

RESUMO

Resistance to therapeutic drugs occurs in virtually all types of cancers, and the tolerance to one drug frequently becomes broad therapy resistance; however, the underlying mechanism remains elusive. Combining a whole whole-genome-wide RNA interference screening and an evolutionary drug pressure model with MDA-MB-231 cells, it is found that enhanced protein damage clearance and reduced mitochondrial respiratory activity are responsible for cisplatin resistance. Screening drug-resistant cancer cells and human patient-derived organoids for breast and colon cancers with many anticancer drugs indicates that activation of mitochondrion protein import surveillance system enhances proteasome activity and minimizes caspase activation, leading to broad drug resistance that can be overcome by co-treatment with a proteasome inhibitor, bortezomib. It is further demonstrated that cisplatin and bortezomib encapsulated into nanoparticle further enhance their therapeutic efficacy and alleviate side effects induced by drug combination treatment. These data demonstrate a feasibility for eliminating broad drug resistance by targeting its common mechanism to achieve effective therapy for multiple cancers.

12.
Small ; 16(39): e2002939, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32875678

RESUMO

The incidence of triple-negative breast cancer (TNBC) is difficult to predict, and TNBC has a high mortality rate among women worldwide. In this study, a theranostics approach is developed for TNBC with ratiometric photoacoustic monitored thiol-initiated hydrogen sulfide (H2 S) therapy. The ratiometric photoacoustic (PA) probe (CY) with a thiol-initiated H2 S donor (PSD) to form a nanosystem (CY-PSD nanoparticles) is integrated. In this theranostics approach, H2 S generated from PSD is sensed by CY based on ratiometric PA signals, which simultaneously pinpoints the tumor region. Additionally, H2 S is cytotoxic toward TNBC cells (MDA-MB 231), showing a tumor inhibition rate of 63%. To further verify its pharmacological mechanism, proteomics analysis is performed on tumors treated with CY-PSD nanoparticles. Cells are killed by the significant mitochondrial dysfunction via supressed energy supply and apoptosis initiation. Besides, the observed inhibition of oxidative stress also generates the cytotoxicity. Significant Kyoto Encyclopedia of Genes Genomes pathways related to TNBC are found to be inhibited. This H2 S theranostics approach updates the current anticancer therapies which brings promise for women suffering malignant breast cancer.


Assuntos
Antineoplásicos , Técnicas Fotoacústicas , Medicina de Precisão , Sulfetos , Neoplasias de Mama Triplo Negativas , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Feminino , Humanos , Medicina de Precisão/instrumentação , Sulfetos/química , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Microambiente Tumoral
13.
Nat Biomed Eng ; 4(11): 1102-1116, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32807941

RESUMO

Cancer immunotherapies, particularly therapeutic vaccination, do not typically generate robust anti-tumour immune responses. Here, we show that the intratumoral burst release of the protein annexin A5 from intravenously injected hollow mesoporous nanoparticles made of diselenide-bridged organosilica generates robust anti-tumour immunity by exploiting the capacity of primary tumours to act as antigen depots. Annexin A5 blocks immunosuppressive apoptosis and promotes immunostimulatory secondary necrosis by binding to the phagocytic marker phosphatidylserine on dying tumour cells. In mice bearing large established tumours, the burst release of annexin A5 owing to diselenide-bond cleavage under the oxidizing conditions of the tumour microenvironment and the reducing intracellular conditions of tumour cells induced systemic cytotoxic T-cell responses and immunological memory associated with tumour regression and the prevention of relapse, and led to complete tumour eradication in about 50% of mice with orthotopic breast tumours. Reducing apoptosis signalling via in situ vaccination could be a versatile strategy for the generation of adaptive anti-tumour immune responses.


Assuntos
Anexina A5/administração & dosagem , Antineoplásicos/administração & dosagem , Apoptose/efeitos dos fármacos , Sistemas de Liberação de Medicamentos/métodos , Imunoterapia/métodos , Neoplasias/terapia , Fagocitose/efeitos dos fármacos , Linfócitos T/efeitos dos fármacos , Animais , Anexina A5/química , Anexina A5/imunologia , Antineoplásicos/química , Antineoplásicos/imunologia , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/terapia , Feminino , Melanoma/imunologia , Melanoma/terapia , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Neoplasias/imunologia , Linfócitos T/imunologia
14.
Biomacromolecules ; 21(9): 3887-3897, 2020 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-32786533

RESUMO

In this study, we report dual roles for doxorubicin (DOX), which can serve as an antitumor drug as well as a cocatalyst for a photoliving radical polymerization. DOX enhances the polymerization rates of a broad range of monomers, including acrylamide, acrylate, and methacrylates, allowing for high monomer conversion and well-defined molecular weights under irradiation with a blue light-emitting diode light (λmax = 485 nm, 2.2 mW/cm2). Utilizing this property, the photopolymerization of N,N-diethylacrylamide was performed in the presence of a poly(oligo(ethylene glycol) methyl ether acrylate) macroreversible addition-fragmentation chain transfer (macroRAFT) agent to prepare polymeric nanoparticles via aqueous polymerization-induced self-assembly (PISA). By varying the monomer:macroRAFT ratio, spherical polymeric nanoparticles of various diameters could be produced. Most notably, DOX was successfully encapsulated into the hydrophobic core of nanoparticles during the PISA process. The DOX-loaded nanoparticles were effectively uptaken into tumor cells and significantly inhibited the proliferation of tumor cells, demonstrating that the DOX bioactivity was not affected by the polymerization reaction.


Assuntos
Doxorrubicina , Nanopartículas , Doxorrubicina/farmacologia , Interações Hidrofóbicas e Hidrofílicas , Metacrilatos , Polimerização , Polímeros
15.
Mol Pharm ; 17(10): 3720-3729, 2020 10 05.
Artigo em Inglês | MEDLINE | ID: mdl-32633977

RESUMO

The limited tumor tissue penetration of many nanoparticles remains a formidable challenge to their therapeutic efficacy. Although several photonanomedicines have been applied to improve tumor penetration, the first near-infrared window mediated by the low optical tissue penetration depth severely limits their anticancer effectiveness. To achieve deep optical tissue and drug delivery penetration, a near-infrared second window (NIR-II)-excited and pH-responsive ultrasmall drug delivery nanoplatform was fabricated based on BSA-stabilized CuS nanoparticles (BSA@CuS NPs). The BSA@CuS NPs effectively encapsulated doxorubicin (DOX) via strong electrostatic interactions to form multifunctional nanoparticles (BSA@CuS@DOX NPs). The BSA@CuS@DOX NPs had an ultrasmall size, which allowed them to achieve deeper tumor penetration. They also displayed stronger NIR II absorbance-mediated deep optical tissue penetration than that of the NIR I window. Moreover, the multifunctional nanoplatform preferentially accumulated in tumor sites, induced tumor hyperthermia, and generated remarkably high ROS levels in tumor sites upon NIR-II laser (1064 nm) irradiation. More importantly, our strategy achieved excellent synergistic effects of chemotherapy and phototherapy (chemophototherapy) under the guidance of photothermal imaging. The developed nanoparticles also showed good biocompatibility and bioclearance properties. Therefore, our work demonstrated a facile strategy for fabricating a multifunctional nanoplatform that is a promising candidate for deep tumor penetration as an effective antitumor therapy.

16.
Biomaterials ; 236: 119803, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32028170

RESUMO

Nanobubbles, as a kind of new ultrasound contrast agent (UCAs), have shown promise to penetrate tumor vasculature to allow for targeted imaging. However, their inherent physical instability is an ongoing concern that could weaken their imaging ability with ultrasound. Gas vesicles (GVs), which are genetically encoded, naturally stable nanostructures, have been developed as the first ultrasonic biomolecular reporters which showed strong contrast enhancement. However, further development of tumor imaging with GVs is limited by the quick clearance of GVs by the reticuloendothelial system (RES). Here, we developed PEGylated HA-GVs (PH-GVs) for in-tumor molecular ultrasound imaging by integrating polyethylene glycol (PEG) and hyaluronic acid (HA) in GV shells. PH-GVs were observed to accumulate around CD44-positive cells (SCC7) but not be internalized by macrophage cell line RAW 264.7. Green fluorescence from PH-GVs was found around cell nuclei in the tumor site after 6 h and the signal was sustained over 48 h following tail injection, demonstrating PH-GVs' ability to escape the clearance from the RES and to penetrate tumor vasculature through enhanced permeability and retention (EPR) effects. Further, PH-GVs produced strong ultrasound contrast in the tumor site in vivo, with no obvious side-effects detected following intravenous injection. Thus, we demonstrate the potential of PH-GVs as novel, nanosized and targeted UCAs for efficient and specific molecular tumor imaging, paving the way for the application of GVs in precise and personalized medicine.


Assuntos
Nanoestruturas , Neoplasias , Linhagem Celular Tumoral , Meios de Contraste , Humanos , Imagem Molecular , Neoplasias/diagnóstico por imagem , Ultrassonografia
17.
ACS Appl Mater Interfaces ; 11(51): 47659-47670, 2019 Dec 26.
Artigo em Inglês | MEDLINE | ID: mdl-31713407

RESUMO

The development of a stimulus-responsive nanosystem provides an effective method for improving the accuracy and efficiency of chemotherapy. Meanwhile, traditional photodynamic therapy (PDT) has been substantially restricted by the low dosage of photosensitizer and limited penetration depth of the ultraviolet (UV) or visible light used for excitation. Here, we designed a smart multifunctional nanoplatform by coating core-shell composite mesoporous silica-encapsulated upconversion nanoparticles and chlorin e6 (Ce6) with degradable calcium phosphate, followed by the loading of doxorubicin (DOX). In our structure, the as-synthesized nanoplatform exhibits high responsiveness to a low pH value and degrades rapidly in the weakly acidic tumor microenvironment, allowing the quick release of loaded DOX in tumor sites. Interestingly, the loaded DOX, whose release depends on the pH value and positively correlates with the calcium-ion concentration, enables drug release to be monitored in real time. Combined with photosensitizer Ce6-induced PDT triggered by an 808 nm near-infrared light, synergistic chemo-photodynamic therapy is achieved, thus leading to a highly efficient anticancer treatment in vitro and in vivo. Importantly, the inherent properties of rare earth ions (Gd3+, Yb3+, and Nd3+) make the nanoplatform possess UCL, MRI, and CT trimode imaging capabilities, thus achieving a multiple imaging modality-guided synergistic therapy.


Assuntos
Fosfatos de Cálcio/química , Nanopartículas/química , Fotoquimioterapia/métodos , Doxorrubicina/química , Doxorrubicina/uso terapêutico , Células HeLa , Humanos , Estrutura Molecular , Porfirinas/química , Raios Ultravioleta
18.
Theranostics ; 9(24): 7200-7209, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31695762

RESUMO

Reactive oxygen species (ROS)-generating anticancer agents can act through two different mechanisms: (i) elevation of endogenous ROS production in mitochondria, or (ii) formation/delivery of exogenous ROS within cells. However, there is a lack of research on the development of ROS-generating nanosystems that combine endogenous and exogenous ROS to enhance oxidative stress-mediated cancer cell death. Methods: A ROS-generating agent based on polymer-modified zinc peroxide nanoparticles (ZnO2 NPs) was presented, which simultaneously delivered exogenous H2O2 and Zn2+ capable of amplifying endogenous ROS production for synergistic cancer therapy. Results: After internalization into tumor cells, ZnO2 NPs underwent decomposition in response to mild acidic pH, resulting in controlled release of H2O2 and Zn2+. Intriguingly, Zn2+ could increase the production of mitochondrial O2·- and H2O2 by inhibiting the electron transport chain, and thus exerted anticancer effect in a synergistic manner with the exogenously released H2O2 to promote cancer cell killing. Furthermore, ZnO2 NPs were doped with manganese via cation exchange, making them an activatable magnetic resonance imaging contrast agent. Conclusion: This study establishes a ZnO2-based theranostic nanoplatform which achieves enhanced oxidative damage to cancer cells by a two-pronged approach of combining endogenous and exogenous ROS.


Assuntos
Nanopartículas/química , Neoplasias/terapia , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Óxido de Zinco/farmacologia , Zinco/farmacologia , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Difusão Dinâmica da Luz , Humanos , Concentração de Íons de Hidrogênio , Manganês/química , Camundongos , Nanopartículas/ultraestrutura , Povidona , Análise Espectral Raman
19.
Front Oncol ; 9: 883, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31572677

RESUMO

The quantity of programmed cell death-ligand 1 (PD-L1) is regarded as a predicting factor of clinical response to anti-PD-1 axis immunotherapy. However, the expression of PD-L1 and its prognostic value in hepatocellular carcinoma (HCC) patients remain debated. Meanwhile, the molecular features of PD-1's other ligand, namely PD-L2, as well as its correlation with clinicopathological parameters and HCC tumor microenvironment (TME), are still poorly understood. In this study, immunohistochemistry (IHC) data from 304 HCC patients were used to determine the clinicopathological features of PD-L1 and PD-L2 and their correlation with CD8+ T cells in HCC. Moreover, fresh clinical HCC samples were used to identify the immune cell subtypes expressing PD-L1 and PD-L2. By using The Cancer Genome Atlas (TCGA) dataset, we further assessed the correlation between mutation signature, copy number variation (CNV), number of neoepitopes, immune gene expression, immune/stromal cell infiltration to the expression of PD-L1 and PD-L2. While membrane expression of PD-L2 was observed in 19.1% of tumor samples, no obvious expression of PD-L1 was detected on tumor cell membranes. High expression of PD-L2 on tumor membranes and PD-L1 in immune stroma were both significantly associated with poorer overall survival (OS) and disease-free survival (DFS) outcomes. Flow cytometry analysis and immunofluorescence showed that macrophages were the main immune cell subtype expressing both PD-L1 and PD-L2. Moreover, positive expression of PD-Ls was correlated with higher CD8+ T cells infiltration in immune stroma. CNV analysis showed a similarity between PD-L1 and PD-L2 in affecting gene expression. In addition, higher levels of PD-Ls correlated with higher expression of immune related genes, enhanced cytolytic activity, and larger proportions of immune/stromal cell infiltration. Collectively, our study reveals the impact of both PD-L1 and PD-L2 on the HCC tumor microenvironment for the first time, providing insight for new therapeutic options.

20.
Nanoscale Horiz ; 4(2): 426-433, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31565239

RESUMO

A Pt prodrug polyphenol and gadolinium ion loaded cancer theranostics nanoplatform based on mild acidic pH and thermal sensitive polymer was designed for photoacoustic (PA)/ magnetic resonance(MR)/ positron emission tomography (PET) multimodal imaging-guided chemo-photothermal combination therapy. The Pt drug release can be controlled by tumour-specific acidic pH and heat generated by external NIR irradiation. The nanoparticles were stable under normal physiological environment and released the drug under tumour acidic pH and NIR laser irradiation, which can reduce the side effect of drug to normal organs. Moreover, the MR signal can be significantly enhanced (~3-fold increase in T1 relaxivity) under the acidic tumour microenvironment, which is favorable for cancer diagnosis. The nanoparticles exhibited excellent tumour accumulation and led to complete tumour eradication with low power NIR laser irradiation. This promising approach provides a new avenue for imaging-guided combination therapy.

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