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1.
ACS Biomater Sci Eng ; 2021 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-34636537

RESUMO

Photothermal therapy (PTT) using nanoparticles is one of the research hotspots in the field of cancer therapy. However, the thermal resistance of tumor cells and the elimination of nanoparticles by the body's immune system reduce their therapeutic effect. Therefore, it is essential to reduce heat resistance, improve their biocompatibility, and reduce the clearance of the immune system. In this work, we constructed a biomimetic platform for cancer therapy based on heat shock protein (HSP) inhibitors, 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG))-loaded and platelet membrane (PM)-coated mesoporous platinum nanoparticles (MPNPs). First, MPNPs with the properties of chemotherapy and PTT were synthesized to load 17-DMAG (17-DMAG/MPNPs). Then, they were coated with PM for tumor targeting and improved biocompatibility to obtain the final bionic nanotherapy platform 17-DMAG/MPNPs@PM. The results in vivo and in vitro showed that 17-DMAG/MPNPs@PM could accumulate in the tumor and effectively inhibit the growth of tumor cells. Therefore, the biomimetic nanotherapy system is expected to provide new ideas for cancer treatment.

3.
Nat Commun ; 12(1): 4964, 2021 08 16.
Artigo em Inglês | MEDLINE | ID: mdl-34400628

RESUMO

Immunological adjuvants are essential for successful cancer vaccination. However, traditional adjuvants have some limitations, such as lack of controllability and induction of systemic toxicity, which restrict their broad application. Here, we present a light-activable immunological adjuvant (LIA), which is composed of a hypoxia-responsive amphiphilic dendrimer nanoparticle loaded with chlorin e6. Under irradiation with near-infrared light, the LIA not only induces tumour cell lysis and tumour antigen release, but also promotes the structural transformation of 2-nitroimidazole containing dendrimer to 2-aminoimidazole containing dendrimer which can activate dendritic cells via the Toll-like receptor 7-mediated signaling pathway. The LIA efficiently inhibits both primary and abscopal tumour growth and induces strong antigen-specific immune memory effect to prevent tumour metastasis and recurrence in vivo. Furthermore, LIA localizes the immunological adjuvant effect at the tumour site. We demonstrate this light-activable immunological adjuvant offers a safe and potent platform for in situ cancer vaccination.


Assuntos
Adjuvantes Imunológicos/farmacologia , Vacinas Anticâncer/imunologia , Dendrímeros/farmacologia , Vacinação , Animais , Antígenos de Neoplasias , Antitussígenos , Linhagem Celular Tumoral , Células Dendríticas/imunologia , Humanos , Hipóxia , Imunoterapia , Luz , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Células NIH 3T3 , Nanopartículas/química , Metástase Neoplásica/prevenção & controle , Recidiva Local de Neoplasia , Neoplasias/genética , Neoplasias/prevenção & controle , Porfirinas , Transcriptoma
4.
Emerg Microbes Infect ; 10(1): 1638-1648, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34346827

RESUMO

MW33 is a fully humanized IgG1κ monoclonal neutralizing antibody, and may be used for the prevention and treatment of coronavirus disease 2019 (COVID-19). We conducted a randomized, double-blind, placebo-controlled, single-dose, dose-escalation Phase 1 study to evaluate the safety, tolerability, pharmacokinetics (PK), and immunogenicity of MW33. Healthy adults aged 18-45 years were sequentially enrolled into the 4, 10, 20, 40, and 60 mg/kg dose groups and infused with MW33 over 60 ± 15 min and followed for 85 days. All 42 enrolled participants completed the MW33 infusion, and 40 participants completed the 85-day follow-up period. 34 participants received a single infusion of 4 (n = 2), 10 (n = 8), 20 (n = 8), 40 (n = 8), and 60 mg/kg (n = 8) of MW33. 27 subjects in the test groups experienced 78 adverse events (AEs) post-dose, with an incidence of 79.4% (27/34). The most common AEs included abnormal laboratory test results, vascular and lymphatic disorders, and infectious diseases. The severity of AEs was mainly Grade 1 (92 AEs), and three Grade 2 and one Grade 4. The main PK parameters, maximum concentration (Cmax), and area under the concentration-time curve (AUC0-t, and AUC0-∞) in 34 subjects showed a linear kinetic relationship in the range of 10-60 mg/kg. The plasma half-life was approximately 25 days. The positive rates of serum ADAs and antibody titres were low with no evidence of an impact on safety or PK. In conclusion, MW33 was well-tolerated, demonstrated linear PK, with a lower positive rate of serum ADAs and antibody titres in healthy subjects.Trial registration: ClinicalTrials.gov identifier: NCT04427501.Trial registration: ClinicalTrials.gov identifier: NCT04533048.Trial registration: ClinicalTrials.gov identifier: NCT04627584.


Assuntos
Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Antivirais/farmacologia , Antivirais/uso terapêutico , COVID-19/tratamento farmacológico , COVID-19/virologia , SARS-CoV-2/efeitos dos fármacos , Adulto , COVID-19/diagnóstico , COVID-19/imunologia , Análise de Dados , Feminino , Humanos , Masculino , SARS-CoV-2/imunologia , Índice de Gravidade de Doença , Resultado do Tratamento , Adulto Jovem
5.
MAbs ; 13(1): 1953683, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34313527

RESUMO

The global pandemic of COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in widespread social and economic disruption. Effective interventions are urgently needed for the prevention and treatment of COVID-19. Neutralizing monoclonal antibodies (mAbs) have demonstrated their prophylactic and therapeutic efficacy against SARS-CoV-2, and several have been granted authorization for emergency use. Here, we discover and characterize a fully human cross-reactive mAb, MW06, which binds to both SARS-CoV-2 and SARS-CoV spike receptor-binding domain (RBD) and disrupts their interaction with angiotensin-converting enzyme 2 (ACE2) receptors. Potential neutralization activity of MW06 was observed against both SARS-CoV-2 and SARS-CoV in different assays. The complex structure determination and epitope alignment of SARS-CoV-2 RBD/MW06 revealed that the epitope recognized by MW06 is highly conserved among SARS-related coronavirus strains, indicating the potential broad neutralization activity of MW06. In in vitro assays, no antibody-dependent enhancement (ADE) of SARS-CoV-2 infection was observed for MW06. In addition, MW06 recognizes a different epitope from MW05, which shows high neutralization activity and has been in a Phase 2 clinical trial, supporting the development of the cocktail of MW05 and MW06 to prevent against future escaping variants. MW06 alone and the cocktail show good effects in preventing escape mutations, including a series of variants of concern, B.1.1.7, P.1, B.1.351, and B.1.617.1. These findings suggest that MW06 recognizes a conserved epitope on SARS-CoV-2, which provides insights for the development of a universal antibody-based therapy against SARS-related coronavirus and emerging variant strains, and may be an effective anti-SARS-CoV-2 agent.


Assuntos
Anticorpos Monoclonais Humanizados/imunologia , Anticorpos Monoclonais/imunologia , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , COVID-19/imunologia , COVID-19/virologia , Vírus da SARS/imunologia , SARS-CoV-2/imunologia , Sequência de Aminoácidos , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Neutralizantes/química , Anticorpos Neutralizantes/uso terapêutico , Anticorpos Antivirais/química , Anticorpos Antivirais/uso terapêutico , Anticorpos Facilitadores , COVID-19/tratamento farmacológico , COVID-19/terapia , Sequência Conservada , Reações Cruzadas , Epitopos/química , Epitopos/genética , Epitopos/imunologia , Humanos , Modelos Moleculares , Testes de Neutralização , Pandemias , Domínios Proteicos , Domínios e Motivos de Interação entre Proteínas , Vírus da SARS/química , Vírus da SARS/genética , SARS-CoV-2/química , SARS-CoV-2/genética , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/imunologia
6.
Biomaterials ; 275: 120992, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34218050

RESUMO

Postoperative recurrence at the primary site and distant metastasis remains the challenge in treating triple-negative breast cancer due to its unpredictable invasion into adjacent tissues. Although systemic chemotherapy has been extensively adopted to attenuate the recurrence and metastasis, the abundant nutrition supply by blood vessels would promote the rapid proliferation of tumor cells and angiogenesis. Herein, we reported a nutrition deprivation strategy by ambidextrously blocking the residual blood vessels and inhibiting angiogenesis to realize efficient treatment of triple-negative breast cancer. To this end, an injectable hydrogel with photo-responsive property was prepared by using polydopamine crosslinked collagen/silk fibroin composite to deliver thrombin for blocking blood vessels and angiogenesis. In the presence of NIR light, the locked thrombin was released into the blood vessels in the adjacent tissues to promote blood coagulation. In addition, the photothermal effect would reduce the secreting of VEGF for preventing angiogenesis in the adjacent tissues. The in vitro and in vivo results demonstrated that the permanent interruption of nutrient supply by blocking the blood vessels adjacent to the resected tumor and preventing angiogenesis is a promising strategy to prevent the recurrence and metastasis of TNBC.


Assuntos
Hidrogéis , Neoplasias de Mama Triplo Negativas , Linhagem Celular Tumoral , Humanos , Recidiva Local de Neoplasia/prevenção & controle , Neovascularização Patológica
7.
J Int Med Res ; 49(6): 3000605211022279, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34111998

RESUMO

OBJECTIVE: We assessed the clinical effects of high-flow nasal cannula (HFNC) oxygen therapy and a standard oxygen atomizer mask on the respiratory tract in patients with hypostatic pneumonia. METHODS: We included patients with hypostatic pneumonia in this retrospective cohort study. Patients were provided continuous airway humidification by continuous oxygen atomization using either an HFNC or standard oxygen mask. Arterial blood gas analysis, the dyspnea score, inflammatory-related parameters, and adverse events of patients in the two groups were compared. RESULTS: Fifty-five patients had HFNC delivery and 57 had a standard oxygen atomizer mask. After 7 days of treatment, patients in the HFNC group had a higher partial pressure of arterial blood oxygen/fraction of inspired oxygen ratio (268.12±28.44 vs 238.28±30.04) and lower partial pressure of arterial blood carbon dioxide (38.02±8.84 vs 49.27±7.84 mmHg) than those in the standard oxygen mask group. The dyspnea score and inflammatory-related parameters in the HFNC group were significantly lower than those in the standard oxygen mask group. The incidence of adverse events was lower in the HFNC group than in the standard oxygen mask group. CONCLUSION: HFNC therapy relieves clinical symptoms more quickly than a standard oxygen mask and reduces the incidence of adverse events.


Assuntos
Pneumonia , Insuficiência Respiratória , Cânula , Humanos , Máscaras , Oxigênio , Oxigenoterapia , Insuficiência Respiratória/terapia , Estudos Retrospectivos
8.
Neurochem Res ; 46(5): 1203-1213, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33650075

RESUMO

Dysregulated circular RNAs (circRNAs) have been confirmed to partake in the modulation of the glioma progression. Here, we intended to explore the role of circBRAF in glioma and the possible action mechanism. The expression levels of circBRAF, microRNA (miR)-1290 and F-box and WD repeat domain containing 7 (FBXW7) were analyzed by quantitative reverse transcription polymerase chain reaction (qRT-PCR) or western blot. Cell viability was assessed by 3-(4, 5)-dimethylthiazole-2-y1)-2, 5-biphenyl tetrazolium bromide (MTT) assay. Cell cycle distribution was determined by flow cytometry. Cell migration and invasion were evaluated through Trans-well assay. Related protein levels were detected by western blot. Targeted relation among circBRAF, miR-1290 and FBXW7 was validated by dual-luciferase reporter, RNA immunoprecipitation (RIP) and pull-down assays. Xenograft model was constructed to explore the function of circBRAF in vivo. Expression of circBRAF and FBXW7 was decreased in glioma tissues and cells. Upregulation of circBRAF inhibited glioma cell proliferation and metastasis in vitro. MiR-1290 was upregulated in glioma, which was sponged by circBRAF. Besides, circBRAF elevated FBXW7 expression by targeting miR-1290. Introduction of miR-1290 or FBXW7 knockdown could counteract the inhibitory effects of circBRAF upregulation on the malignant phenotypes of glioma cells. Overexpression of circBRAF repressed the tumor growth in vivo. Upregulation of circBRAF suppressed glioma evolvement in vitro and in vivo by regulating miR-1290/FBXW7 axis, broadening the cognition of glioma progression.


Assuntos
Proteína 7 com Repetições F-Box-WD/metabolismo , Glioma/metabolismo , MicroRNAs/metabolismo , RNA Circular/metabolismo , Animais , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Progressão da Doença , Regulação Neoplásica da Expressão Gênica/fisiologia , Humanos , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Invasividade Neoplásica/fisiopatologia , Metástase Neoplásica/fisiopatologia
9.
Biomaterials ; 269: 120654, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33434712

RESUMO

A variety of therapies have been developed and used for the treatment of colon cancer, however, the high mortality rate remains high and more effective strategies are still in urgent needs. In this study, an immunotherapy approach that is composed of innate immune activator Astragaloside III (As) and the photodynamic therapy (PDT) reagent chlorine e6 (Ce6) ((As + Ce6)@MSNs-PEG), was developed for colon cancer treatment. We showed that (As + Ce6)@MSNs-PEG could effectively activate NK cells and inhibit the proliferation of tumor cells in vitro. It could also effectively reach tumor sites, induce infiltration of immune cells into the tumor, and enhance the cytotoxicity of natural killer cells and CD8+ T cells in vivo. Without obvious side effects, (As + Ce6)@MSNs-PEG treatment significantly inhibited tumor growth and extended the lifespan of tumor-bearing mice. Further results revealed that treatment of (As + Ce6)@MSNs-PEG led to enhanced IFN secretion by immune cells and increased T-box transcription factor (T-bet), which is highly expressed by T cells. Therefore, (As + Ce6)@MSNs-PEG may serve as an effective and safe platform for combinatory use with nano-herb medicine and PDT to provide a new therapy for colon cancer treatment.


Assuntos
Neoplasias do Colo , Nanopartículas , Fotoquimioterapia , Porfirinas , Animais , Linfócitos T CD8-Positivos , Linhagem Celular Tumoral , Neoplasias do Colo/tratamento farmacológico , Imunoterapia , Camundongos , Fármacos Fotossensibilizantes/uso terapêutico
10.
Sci China Life Sci ; 64(3): 434-442, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32239367

RESUMO

Excessive reactive oxygen species (ROS) would attack living cells and cause a series of oxidative stress related diseases, such as liver damage. Hydroxyl radicals (·OH) are currently known as one of the most toxic and harmful free radicals to organisms. Therefore, studies involving hydroxyl radicals have become important research topics in the fields of biology, biochemistry, and biomedicine. In addition, imaging of analytes using upconversion nanoparticles (UCNPs) possesses significant advantages over that using general fluorescent dyes or nanoparticles due to its high spatial resolution, reduced photodamage, and deep tissue penetration properties. Herein, we designed a highly selective and sensitive hydroxyl radical nanoprobe based on the luminescence resonance energy transfer between upconversion nanoparticles and methylene blue (MB). The concentration of ·OH could be determined by the fluorescence recovery of the UCNPs due to the oxidative damage of MB. Using this nanoprobe, the ·OH in living cells or in liver tissues could be monitored with high sensitivity and selectivity.

11.
ACS Nano ; 15(1): 1100-1110, 2021 01 26.
Artigo em Inglês | MEDLINE | ID: mdl-33236885

RESUMO

Hypoxia can increase the resistance of tumor cells to radiotherapy and chemotherapy. However, the dense extracellular matrix, high interstitial fluid pressure, and irregular blood supply often serve as physical barriers to inhibit penetration of drugs or nanodrugs across tumor blood microvessels into hypoxic regions. Therefore, it is of great significance and highly desirable to improve the efficiency of hypoxia-targeted therapy. In this work, living photosynthetic bacteria (PSB) are utilized as hypoxia-targeted carriers for hypoxic tumor therapy due to their near-infrared (NIR) chemotaxis and their physiological characteristics as facultative aerobes. More interestingly, we discovered that PSB can serve as a kind of photothermal agent to generate heat through nonradiative relaxation pathways due to their strong photoabsorption in the NIR region. Therefore, PSB integrate the properties of hypoxia targeting and photothermal therapeutic agents in an "all-in-one" manner, and no postmodification is needed to achieve hypoxia-targeted cancer therapy. Moreover, as natural bacteria, noncytotoxic PSB were found to enhance immune response that induced the infiltration of cytotoxicity T lymphocyte. Our results indicate PSB specifically accumulate in hypoxic tumor regions, and they show a high efficiency in the elimination of cancer cells. This proof of concept may provide a smart therapeutic system in the field of hypoxia-targeted photothermal therapeutic platforms.


Assuntos
Hipertermia Induzida , Neoplasias , Sistemas de Liberação de Medicamentos , Humanos , Hipóxia , Neoplasias/tratamento farmacológico , Fototerapia
12.
Nat Commun ; 11(1): 5752, 2020 11 13.
Artigo em Inglês | MEDLINE | ID: mdl-33188207

RESUMO

Efficacious interventions are urgently needed for the treatment of COVID-19. Here, we report a monoclonal antibody (mAb), MW05, with SARS-CoV-2 neutralizing activity by disrupting the interaction of receptor binding domain (RBD) with angiotensin-converting enzyme 2 (ACE2) receptor. Crosslinking of Fc with FcγRIIB mediates antibody-dependent enhancement (ADE) activity by MW05. This activity is eliminated by introducing the LALA mutation to the Fc region (MW05/LALA). Potent prophylactic and therapeutic effects against SARS-CoV-2 are observed in rhesus monkeys. A single dose of MW05/LALA blocks infection of SARS-CoV-2 in prophylactic treatment and clears SARS-CoV-2 in three days in a therapeutic treatment setting. These results pave the way for the development of MW05/LALA as an antiviral strategy for COVID-19.


Assuntos
Anticorpos Monoclonais/imunologia , Anticorpos Neutralizantes/imunologia , Antivirais/farmacologia , Betacoronavirus/imunologia , Infecções por Coronavirus/terapia , Pneumonia Viral/terapia , Glicoproteína da Espícula de Coronavírus/imunologia , Enzima de Conversão de Angiotensina 2 , Animais , Anticorpos Antivirais/imunologia , COVID-19 , Linhagem Celular , Chlorocebus aethiops , Infecções por Coronavirus/prevenção & controle , Feminino , Células HEK293 , Humanos , Macaca mulatta , Masculino , Pandemias/prevenção & controle , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/prevenção & controle , Receptores de IgG/genética , Receptores de IgG/imunologia , Receptores Virais/metabolismo , SARS-CoV-2 , Células Vero , Ligação Viral
13.
Nat Nanotechnol ; 15(12): 1053-1064, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33106640

RESUMO

Cancer vaccines hold great promise for improved cancer treatment. However, endosomal trapping and low immunogenicity of tumour antigens usually limit the efficiency of vaccination strategies. Here, we present a proton-driven nanotransformer-based vaccine, comprising a polymer-peptide conjugate-based nanotransformer and loaded antigenic peptide. The nanotransformer-based vaccine induces a strong immune response without substantial systemic toxicity. In the acidic endosomal environment, the nanotransformer-based vaccine undergoes a dramatic morphological change from nanospheres (about 100 nanometres in diameter) into nanosheets (several micrometres in length or width), which mechanically disrupts the endosomal membrane and directly delivers the antigenic peptide into the cytoplasm. The re-assembled nanosheets also boost tumour immunity via activation of specific inflammation pathways. The nanotransformer-based vaccine effectively inhibits tumour growth in the B16F10-OVA and human papilloma virus-E6/E7 tumour models in mice. Moreover, combining the nanotransformer-based vaccine with anti-PD-L1 antibodies results in over 83 days of survival and in about half of the mice produces complete tumour regression in the B16F10 model. This proton-driven transformable nanovaccine offers a robust and safe strategy for cancer immunotherapy.


Assuntos
Antígenos/administração & dosagem , Vacinas Anticâncer/administração & dosagem , Preparações de Ação Retardada/química , Nanosferas/química , Neoplasias/prevenção & controle , Animais , Antígenos/uso terapêutico , Vacinas Anticâncer/uso terapêutico , Linhagem Celular Tumoral , Feminino , Humanos , Concentração de Íons de Hidrogênio , Imunoterapia , Camundongos , Camundongos Endogâmicos C57BL , Neoplasias/patologia , Polímeros/química , Prótons
14.
J Tradit Chin Med ; 40(4): 509-517, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32744019

RESUMO

OBJECTIVE: To evaluate the effectiveness of Chinese herbal medicine for primary Raynaud's phenomenon (PRP). METHODS: The Cochrane Central Register of Controlled Trials, PubMed, Chinese Biomedical Literature Database, China National Knowledge Infrastructure, China Science and Technology Journal Database, and Wanfang Database were searched up to February 13, 2018. Randomized controlled trials (RCTs) on treatment of PRP with Chinese herbal medicine compared with placebo, blank control, lifestyle changes, or calcium antagonists were identified and reviewed. The quality of included trials was assessed using a risk of bias tool. RESULTS: Eight RCTs involving 674 participants were included. The methodological quality of the included trials was generally poor. Meta-analysis of two trials showed that Buyang Huanwu Tang plus Danggui Sini Tang produced greater improvement in global symptoms than nifedipine. One trial showed that Danggui Sini Tang and a self-composed Chinese herbal medicine decoction, respectively, produced greater improvement in global symptoms than nifedipine alone. In one trial, modified Danggui Sini Tang showed greater improvement in global symptoms and arterial peak systolic velocity compared with nifedipine. One trial showed that Jiejing Tongmi Tang produced greater improvement in global symptoms, plasma endothelin, and plasma nitric oxide than cinepazide maleate injection. However, Jiejing Tongmi Tang did not produce a significant difference in skin temperature and peripheral artery blood stream drawing after cold pressor testing compared with cinepazide maleate injection. None of the trials reported frequency of attacks, duration of attacks, participant preference scores, or adverse events. CONCLUSION: Chinese herbal medicine may have a positive effective on PRP. However, owing to weak methodology, the benefits of Chinese herbal medicine for PRP are inconclusive. More rigorously designed studies are needed to confirm these findings.

15.
J Struct Biol ; 212(1): 107593, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32736072

RESUMO

Akkermansia muciniphila is a beneficial microorganism colonized in the human gut that can reverse many intestinal metabolic-related diseases. Amuc_1100 is an outer-membrane protein of A. muciniphila. Oral administration of Amuc_1100 can reduce fat mass development, insulin resistance, and dyslipidemia in mice and activated the toll-like receptor 2 (TLR2) to regulate the immune response of the host, but the molecular mechanism remains unclear. Here we report the crystal structure of the extramembranous domain of Amuc_1100, which consists of a four-stranded antiparallel ß-sheet and four α-helices. Two C-terminal helices and the four-stranded antiparallel ß-sheet formed two "αßß" motifs and constituted the core domain, which shared a similar fold with type IV pili and type II Secretion system protein. Although the full-length of the extramembranous domain of Amuc_1100 existed as a monomer in solution, they formed trimer in the crystal. Elimination of the N-terminal coiled-coil helix α1 led to dimerization of Amuc_1100 both in solution and in crystal, indicating that the oligomeric state of Amuc_1100 was variable and could be influenced by α1. In addition, we identified that Amuc_1100 could directly bind human TLR2 (hTRL2) in vitro, suggesting that Amuc_1100 may serve as a new ligand for hTLR2. Dimerization of Amuc_1100 improved its hTLR2-binding affinity, suggesting that the α1-truncated Amuc_1100 could be a beneficial candidate for the development of A. muciniphila related drugs.

16.
ACS Appl Mater Interfaces ; 12(31): 34667-34677, 2020 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-32610896

RESUMO

Efficient drug delivery into tumor cells while bypassing many biological barriers is still a challenge for cancer therapy. By taking advantage of the palladium (Pd)-mediated in situ activation of a prodrug and the glucose oxidase (GOD)-based ß-d-glucose oxidation reaction, we developed a multisynergistic cancer therapeutic platform that combined doxorubicin (DOX)-induced chemotherapy with GOD-mediated cancer-orchestrated oxidation therapy and cancer starvation therapy. In the present work, we first synthesized DOX prodrugs (pDOXs) and temporarily assembled them with ß-cyclodextrins to reduce their toxic side effects. Then, a nanoreactor was constructed by synthesizing Pd0 nanoparticles in situ within the pores of mesoporous silica nanoparticles for the conversion of pDOX into the active anticancer drug. Furthermore, GOD was introduced to decrease the pH of the tumor microenvironment and induce cancer-orchestrated oxidation/starvation therapy by catalyzing ß-d-glucose oxidation to form hydrogen peroxide (H2O2) and gluconic acid. Our study provides a new strategy that employs a cascade chemical reaction to achieve combined orchestrated oxidation/starvation/chemotherapy for the synergistic killing of cancer cells and the suppression of tumor growth.


Assuntos
Antibióticos Antineoplásicos/uso terapêutico , Doxorrubicina/uso terapêutico , Nanopartículas/química , Pró-Fármacos/uso terapêutico , Animais , Antibióticos Antineoplásicos/síntese química , Antibióticos Antineoplásicos/química , Doxorrubicina/síntese química , Doxorrubicina/química , Feminino , Glucose Oxidase/química , Glucose Oxidase/metabolismo , Humanos , Concentração de Íons de Hidrogênio , Células MCF-7 , Neoplasias Mamárias Experimentais/tratamento farmacológico , Neoplasias Mamárias Experimentais/metabolismo , Neoplasias Mamárias Experimentais/patologia , Camundongos , Camundongos Nus , Estrutura Molecular , Paládio/química , Tamanho da Partícula , Pró-Fármacos/síntese química , Pró-Fármacos/química , Propriedades de Superfície
17.
Theranostics ; 10(13): 5649-5670, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32483410

RESUMO

The unique features of noble-metal nanostructures (NMNs) are leading to unprecedented expansion of research and exploration of their application in therapeutics, diagnostics and bioimaging fields. With the ever-growing applications of NMNs, both therapeutic and environmental NMNs are likely to be exposed to tissues and organs, requiring careful studies towards their biological effects in vitro and in vivo. Upon NMNs exposure, tissues and cells may undergo a series of adaptive changes both in morphology and function. At the cellular level, the accumulation of NMNs in various subcellular organelles including lysosomes, endoplasmic reticulum, Golgi apparatus, mitochondria, and nucleus may interfere with their functions, causing changes in a variety of cellular functions, such as digestion, protein synthesis and secretion, energy metabolism, mitochondrial respiration, and proliferation. In animals, retention of NMNs in metabolic-, respiratory-, immune-related, and other organs can trigger significant physiological and pathological changes to these organs and influence their functions. Exploring how NMNs interact with tissues and cells and the underlying mechanisms are of vital importance for their future applications. Here, we illustrate the characteristics of NMNs-induced adaptive changes both in vitro and in vivo. Potential strategies in the design of NMNs are also discussed to take advantage of beneficial adaptive changes and avoid unfavorable changes for the proper implementation of these nanoplatforms.

18.
ACS Appl Mater Interfaces ; 12(24): 26832-26841, 2020 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-32449617

RESUMO

Although considerable clinical attempts on various kinds of cancers have been made, photodynamic therapy (PDT) still suffers from attenuated therapeutic effects because of the developed resistance of cancer cells. As a novel antiapoptosis protein, survivin has been demonstrated to be selectively overexpressed in a great number of human malignancies and plays a significant part in cancer progression and therapeutic resistance. Herein, we present an upconversion nanoplatform for enhanced PDT by DNAzyme-mediated gene silencing of survivin. In our system, a long single-stranded DNA (ssDNA) with a repetitive aptamer (AS1411) and survivin-targeted DNAzyme was fabricated by rolling circle amplification (RCA) and adsorbed on the upconversion nanoparticles (UCNPs) by electrostatic attraction. The multivalence of the ssDNA endows the upconversion nanoplatform with high recognition and loading capacity of photosensitizers and DNAzymes. When the nanoplatform is targeted internalized into cancer cells, PDT can be triggered by near-infrared (NIR) light to generate reactive oxygen species (ROS) for killing the cancer cells. Moreover, the encoded DNAzyme can efficiently inhibit the gene expression of survivin, providing the potential to enhance the efficiency of PDT. This study thus highlights the promise of an upconversion photodynamic nanoplatform for admirable combination therapy in cancer.


Assuntos
DNA Catalítico/química , Fotoquimioterapia/métodos , Polímeros/química , DNA Catalítico/metabolismo , Inativação Gênica/fisiologia , Humanos , Nanopartículas/química , Neoplasias/terapia
19.
J Mater Chem B ; 8(18): 3985-4001, 2020 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-32239013

RESUMO

Cancer stem cells (CSCs) exhibit high resistance to conventional therapy and are responsible for cancer metastasis and tumor relapse. Therefore, it is of significance to develop effective novel strategies to target CSCs for cancer therapies. The challenges associated with developing novel strategies include specific CSC targeting and overcoming their therapeutic resistance. In the present review, we summarize the various strategies for CSC-targeted cancer thermotherapy and combinational therapy, and the potential challenges and prospects for future work in this emerging field.


Assuntos
Antineoplásicos/farmacologia , Nanomedicina , Nanopartículas/química , Células-Tronco Neoplásicas/efeitos dos fármacos , Terapia Fototérmica , Animais , Antineoplásicos/química , Humanos , Tamanho da Partícula , Propriedades de Superfície
20.
Theranostics ; 10(11): 4944-4957, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32308760

RESUMO

Due to their lower systemic toxicity, faster kidney clearance and higher tumor accumulation, ultrasmall gold nanoparticles (less than 10 nm in diameter) have been proved to be promising in biomedical applications. However, their potential applications in cancer imaging and treatment have not been reviewed yet. This review summarizes the efforts to develop systems based on ultrasmall gold nanoparticles for use in cancer diagnosis and therapy. First, we describe the methods for controlling the size and surface functionalization of ultrasmall gold nanoparticles. Second, we review the research on ultrasmall gold nanoparticles in cancer imaging and treatment. Specifically, we focus on the applications of ultrasmall gold nanoparticles in tumor visualization and bioimaging in different fields such as magnetic resonance imaging, photoacoustic imaging, fluorescence imaging, and X-ray scatter imaging. We also highlight the applications of ultrasmall gold nanoparticles in tumor chemotherapy, radiotherapy, photodynamic therapy and gene therapy.


Assuntos
Ouro , Nanopartículas Metálicas , Neoplasias , Animais , Linhagem Celular Tumoral , Terapia Genética , Ouro/farmacologia , Ouro/uso terapêutico , Humanos , Imageamento por Ressonância Magnética , Nanopartículas Metálicas/química , Nanopartículas Metálicas/uso terapêutico , Neoplasias/diagnóstico por imagem , Neoplasias/tratamento farmacológico , Neoplasias/radioterapia , Imagem Óptica , Técnicas Fotoacústicas , Fotoquimioterapia , Tomografia por Emissão de Pósitrons , Espalhamento de Radiação
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