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1.
Anal Chem ; 93(42): 14351-14357, 2021 10 26.
Artigo em Inglês | MEDLINE | ID: mdl-34648255

RESUMO

Biofouling has been a substantial burden on biomarker analysis in complex biological media, leading to poor sensitivity and selectivity or even malfunction of the sensing devices. In this work, an electrochemical biosensor with excellent antifouling ability and high stability was fabricated based on amyloid-like bovine serum albumin (AL-BSA) crosslinked with the conducting polymer polyaniline (PANI). Compared with the crosslinked conventional bovine serum albumin (BSA), the crosslinked AL-BSA exhibited enhanced antifouling capability, and it was able to form an effective antifouling film within a significantly short reaction time. With further immobilization of immunoglobulin M (IgM) antibodies onto the prepared AL-BSA surface via the formation of amide bonds, an electrochemical biosensor capable of assaying IgM in human serum samples with superior selectivity and sensitivity was constructed. The biosensor exhibited excellent antifouling performance even in 100% human serum, a low limit of detection down to 2.32 pg mL-1, and acceptable accuracy for real sample analysis compared with the standard enzyme-linked immunosorbent assay for IgM detection. This strategy of using AL-BSA to construct antifouling sensing interfaces provided a reliable diagnostic method for the detection of a series of protein biomarkers in complex biological media.


Assuntos
Incrustação Biológica , Técnicas Biossensoriais , Incrustação Biológica/prevenção & controle , Técnicas Eletroquímicas , Humanos , Peptídeos , Polímeros , Soroalbumina Bovina
2.
PLoS Pathog ; 17(9): e1009901, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34506605

RESUMO

Neddylation, an important type of post-translational modification, has been implicated in innate and adapted immunity. But the role of neddylation in innate immune response against RNA viruses remains elusive. Here we report that neddylation promotes RNA virus-induced type I IFN production, especially IFN-α. More importantly, myeloid deficiency of UBA3 or NEDD8 renders mice less resistant to RNA virus infection. Neddylation is essential for RNA virus-triggered activation of Ifna gene promoters. Further exploration has revealed that mammalian IRF7undergoes neddylation, which is enhanced after RNA virus infection. Even though neddylation blockade does not hinder RNA virus-triggered IRF7 expression, IRF7 mutant defective in neddylation exhibits reduced ability to activate Ifna gene promoters. Neddylation blockade impedes RNA virus-induced IRF7 nuclear translocation without hindering its phosphorylation and dimerization with IRF3. By contrast, IRF7 mutant defective in neddylation shows enhanced dimerization with IRF5, an Ifna repressor when interacting with IRF7. In conclusion, our data demonstrate that myeloid neddylation contributes to host anti-viral innate immunity through targeting IRF7 and promoting its transcriptional activity.


Assuntos
Imunidade Inata/imunologia , Fator Regulador 7 de Interferon/imunologia , Células Mieloides/imunologia , Infecções por Vírus de RNA/imunologia , Vírus de RNA/imunologia , Animais , Fator Regulador 7 de Interferon/biossíntese , Camundongos , Células Mieloides/metabolismo , Proteína NEDD8/deficiência , Processamento de Proteína Pós-Traducional , Ubiquitinas/deficiência
3.
J Immunol ; 207(5): 1411-1418, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34348973

RESUMO

The receptor for activated C kinase 1 (RACK1) adaptor protein has been implicated in viral infection. However, whether RACK1 promotes in vivo viral infection in mammals remains unknown. Moreover, it remains elusive how RACK1 is engaged in antiviral innate immune signaling. In this study, we report that myeloid RACK1 deficiency does not affect the development and survival of myeloid cells under resting conditions but renders mice less susceptible to viral infection. RACK1-deficient macrophages produce more IFN-α and IFN-ß in response to both RNA and DNA virus infection. In line with this, RACK1 suppresses transcriptional activation of type 1 IFN gene promoters in response to virus infection. Analysis of virus-mediated signaling indicates that RACK1 inhibits the phosphorylation of IRF3/7. Indeed, RACK1 interacts with IRF3/7, which is enhanced after virus infection. Further exploration indicates that virus infection triggers AMPK activation, which in turn phosphorylates RACK1 at Thr50 RACK1 phosphorylation at Thr50 enhances its interaction with IRF3/7 and thereby limits IRF3/7 phosphorylation. Thus, our results confirm that myeloid RACK1 promotes in vivo viral infection and provide insight into the control of type 1 IFN production in response to virus infection.


Assuntos
Proteínas Quinases Ativadas por AMP , Fator Regulador 3 de Interferon , Proteínas Adaptadoras de Transdução de Sinal , Animais , Fator Regulador 3 de Interferon/genética , Fator Regulador 3 de Interferon/metabolismo , Interferon beta/metabolismo , Camundongos , Fosforilação , Receptores de Quinase C Ativada , Transdução de Sinais
4.
Biomaterials ; 275: 120958, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34130142

RESUMO

Tumor-associated macrophages (TAMs) in the tumor microenvironment (TME) play an important role in the development of tumors by secreting a variety of cytokines or directly communicating with tumor cells, making TAMs-targeted therapeutic strategies very attractive. It has been reported that oncogene c-Myc is related to every aspect of the oncogenic process of tumor cells and the alternative activation of macrophages. Hence, we constructed a glycolipid nanocarrier containing ROS-responsive peroxalate linkages (CSOPOSA) for ROS-triggered release of drugs and further modified it with Ex 26 (Ex 26-CSOPOSA), a selective sphingosine 1-phosphate receptor 1 (S1PR1) antagonist, to achieve the dual-targeted delivery of the c-Myc inhibitor JQ1 via S1PR1, which is overexpressed on both tumor cells and TAMs, thereby inducing apoptosis of tumor cells, and blocking M2 polarization of macrophages. More strikingly, our studies found that JQ1 could effectively inhibit the migration of tumor cells induced by M2 macrophages-derived exosomes via blocking Caveolin-1 related intercellular exosome exchange through lncRNA H19 and miR-107. The in vivo results revealed that this dual-targeted delivery strategy effectively inhibited tumor growth and metastasis with less systemic toxicity, providing a potential method for effective tumor treatment.


Assuntos
Caveolina 1 , Exossomos , Neoplasias Experimentais/tratamento farmacológico , Espécies Reativas de Oxigênio , Animais , Linhagem Celular Tumoral , Portadores de Fármacos , Liberação Controlada de Fármacos , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Proteínas Proto-Oncogênicas c-myc , Células RAW 264.7 , Microambiente Tumoral
5.
Mol Ther Nucleic Acids ; 24: 127-139, 2021 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-33738144

RESUMO

Hepatitis B (HB) is a viral infectious disease that seriously endangers human health, and since there are no radical drugs to counter this, effective and safe therapies urgently need to be developed. HB virus (HBV) mainly infects hepatocytes (HCs), while the drugs are easily phagocytosed by Kupffer cells (KCs). In this study, the glutathione concentration difference between HCs and KCs was examined and utilized in an ideal drug-release strategy. Here, galactosylated chitosan-oligosaccharide-SS-octadecylamine (Gal-CSSO) was prepared to accurately deliver 10-23 DNAzyme DrzBC (blocking HBeAg expression) or DrzBS (blocking HBsAg expression) in targeted HB therapy. In vitro Gal-CSSO systems exhibited low cytotoxicity, endosomal escape, and glutathione responsiveness. The HBeAg and HBsAg secretion of HepG2.2.15 was significantly decreased by Gal-CSSO systems, and the maximum inhibition rates were 1.82-fold and 2.38-fold greater than those of commercial Lipofectamine 2000 (Lipo2000) systems. In vivo Gal-CSSO systems exhibited HC targeting and HC microenvironmental responsiveness without noticeable hepatotoxicity or systemic toxicity. The HBeAg and HBsAg titers of the HBV-infected mice were evidently decreased by Gal-CSSO systems, and the inhibition rates were 1.52-fold and 1.22-fold greater than those of Lipo2000 systems. This study presents a kind of glycolipid-like polymer micelles that promise efficient and safe gene therapy of HB.

6.
Carbohydr Polym ; 240: 116270, 2020 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-32475559

RESUMO

Tumor-draining lymph node (TDLN), already bathed in tumor antigens, has been proposed as an intriguing site for cancer immunotherapy. Targeted delivery of adjuvants to TDLN, presumably could induce antitumor immunity for personalized immunotherapy. Although molecular adjuvants can be used for personalized immunotherapy, their efficacy is limited by insufficient antigen uptake by dendritic cells (DCs). In contrast, nanomaterial-based adjuvants can enhance antigen uptake by DCs by capturing antigens. Herein, mannose modified stearic acid-grafted chitosan micelles (MChSA), which presumably could target TDLN, were engineered to capture endogenous antigens and enhance antigen uptake by DCs for personalized immunotherapy. MChSA micelles showed strong antigen-capturing and TDLN targeting ability. Importantly, MChSA micelles induced robust CD4+ and CD8+ T cell responses, stimulated antitumor related cytokine secretion and notably inhibited tumor growth. MChSA micelles, which can target TDLN to induce potent antitumor immune responses as antigen-capturing adjuvants, exhibit great potential in personalized cancer immunotherapy.


Assuntos
Adjuvantes Imunológicos/uso terapêutico , Quitosana/química , Células Dendríticas/efeitos dos fármacos , Linfonodos , Neoplasias/terapia , Animais , Linhagem Celular Tumoral , Células Dendríticas/citologia , Imunoterapia , Linfonodos/efeitos dos fármacos , Linfonodos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Micelas
7.
Biomacromolecules ; 21(7): 2818-2828, 2020 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-32496052

RESUMO

Lymph nodes are proposed as the intriguing target in cancer immunotherapy, and cellular immunity is vital for vaccines to fight against cancer. However, inefficient delivery of vaccines to lymph nodes and deficient lysosomal escape of antigens result in weak cellular immunity, which restrains the strength of vaccines in inducing antitumor immune responses. Hence, dendritic cell membrane (DCM)/histidine-modified stearic acid-grafted chitosan (HCtSA)/ovalbumin (OVA) micelles, as pH-responsive biomimetic vaccines, were fabricated to target lymph nodes and induce cellular immunity for enhanced antitumor immune responses. DCM/HCtSA/OVA micelles exhibited pH-dependent antigen release behavior, which resulted in efficient escape of antigens from dendritic cell (DC) lysosomes. Besides, DCM/HCtSA/OVA micelles accumulated and reserved in the lymph nodes, which ensured effective uptake by DCs. Importantly, DCM/HCtSA/OVA micelles induced potent T cell immune responses, promoted secretion of antitumor-related cytokines, and notably inhibited tumor growth. Overall, DCM/HCtSA/OVA micelles exhibit great potential in targeted immunotherapy and can provide guidance for the design of vaccines.


Assuntos
Vacinas Anticâncer , Vacinas , Animais , Antígenos , Biomimética , Células Dendríticas , Concentração de Íons de Hidrogênio , Imunidade Celular , Linfonodos , Camundongos , Camundongos Endogâmicos C57BL , Micelas , Ovalbumina
8.
Signal Transduct Target Ther ; 5(1): 82, 2020 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-32467564

RESUMO

Although targeted therapy has been extensively investigated for breast cancers, a molecular target with broad application is currently unavailable due to the high heterogeneity of these cancers. Mammaglobin-A (Mam-A), which is overexpressed in most breast carcinomas, has been proposed as a promising target. However, the lack of specific targeting moieties due to uncertain binding epitopes hampers further translational study. Here, seven potential epitopes of Mam-A were disclosed, and a unique epitope was then identified in most types of breast cancers, despite the genotypic heterogeneity. With phage display technology, the epitope was determined to be N-terminal amino acids 42-51 of Mam-A (N42-51). Then, the N42-51 epitope-specific monoclonal antibody, mAb785, was conjugated to poly lactic-co-glycolic acid (PLGA) nanoparticles loaded with therapeutic agents, thereby enhancing the drug uptake and therapeutic efficacy in different genotypes of breast cancers. The computer simulation of the N42-51 epitope and the mAb785 structures, as well as their interactions, further revealed the specific targeting mechanism of the mAb785-conjugated nanoparticles to breast cancers.


Assuntos
Anticorpos Monoclonais/farmacologia , Antineoplásicos Imunológicos/farmacologia , Neoplasias da Mama/terapia , Mamoglobina A/farmacologia , Anticorpos Monoclonais/imunologia , Antineoplásicos Imunológicos/imunologia , Neoplasias da Mama/genética , Neoplasias da Mama/imunologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Linhagem Celular Tumoral , Epitopos/genética , Epitopos/imunologia , Feminino , Humanos , Mamoglobina A/genética , Mamoglobina A/imunologia , Nanopartículas/química , Proteínas de Neoplasias/genética , Linfócitos T Citotóxicos/efeitos dos fármacos , Linfócitos T Citotóxicos/imunologia
9.
Carbohydr Polym ; 229: 115435, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31826424

RESUMO

Micelles are one of the most investigated nanocarriers for drug delivery. In this study, polymeric micelles based on chitosan were prepared to explore the delivery mechanism which was critical for enhancing tumor targeting but still remain elusive. The chitosan polymer COSA was synthesized and the polymeric micelles showed good self-assembly ability, good dispersion stability and low toxicity. After being intravenously administered, the micelles were selectively taken up by circulating monocytes in a receptor-mediated way (almost 94% uptake in Ly-6Chi monocytes, below 7% in all other circulating cells) and reach the tumor with the subsequent travel of these cells. In addition, the micelles in macrophages (differentiated from circulating monocytes) can be exocytosed and subsequently taken up by cancer cells. The delivery mechanism of COSA micelles is directional for the novel strategies to enhance tumor targeting and the micelles are promising candidates for diseases in which monocytes are directly implicated.


Assuntos
Quitosana/metabolismo , Portadores de Fármacos/metabolismo , Micelas , Monócitos/metabolismo , Animais , Antineoplásicos/farmacologia , Doxorrubicina/farmacologia , Liberação Controlada de Fármacos , Endocitose , Exocitose , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Neoplasias/metabolismo , Células RAW 264.7
10.
ACS Biomater Sci Eng ; 6(5): 3217-3229, 2020 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-33463256

RESUMO

High invasion and metastasis are the major obstacles to successful breast cancertherapy. Indocyanine green (ICG), a photosensitizer for photothermal therapy (PTT), shows potent anticancer efficacy when combined with the chemotherapeutic drug doxorubicin (DOX). Human serum albumin (HSA), a biocompatible carrier material, has been successfully used for the delivery of paclitaxel (Abraxane). In addition, there are ICG functional binding regions in HSA. Thus, a smart assembled nanoplatform (DI@HSA NPs) was constructed to achieve the synergistic effects of chemo- photothermal therapy against breast cancer. Compared to free ICG and free DOX, DI@HSA NPs showed satisfactory stability and exhibited an enhanced tumor targeting capacity. The mild hyperthermia generated by DI@HSA NPs can not only cause tumor photothermal ablation and promote the uptake of DI@HSA NPs by 4T1 cells, but also protect the healthy tissues nearby the tumor from overheating injury. More importantly, DI@HSA NPs greatly amplified the infiltration of CD4+ T cells and CD8+ T cells, resulting in inhibited tumor growth and metastasis. DI@HSA NPs, as a simple biocompatible nanoagent, showed excellent inhibition of breast cancer growth and metastasis by chemo-photothermal therapy, providing a potential strategy for the future therapy of breast cancer.


Assuntos
Neoplasias da Mama , Hipertermia Induzida , Neoplasias da Mama/tratamento farmacológico , Linfócitos T CD8-Positivos , Humanos , Terapia Fototérmica , Albumina Sérica Humana
11.
Carbohydr Polym ; 212: 215-221, 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-30832850

RESUMO

DrzBC and DrzBS (10-23 DNAzyme) could block the expression of HBV e- and s- gene respectively. But the application of 10-23 DNAzyme was limited owing to the lack of appropriate delivery vehicles. Chitosan oligosaccharide-SS-Octadecylamine (CSSO), a redox-responsive nano-sized polymeric carrier, could self-aggregate and bind with DNA by electrostatic interaction at proper mass ratio. Compared with the traditional commercial carrier Lipo2000, CSSO exhibited lower cytotoxicity, efficient cellular uptake by targeting cells, and rapidly DNA released in cytoplasm after escaping from endosomes. Including the same DNA concentration, Lipo2000/(DrzBC or DrzBS) showed maximum inhibitory rate on HBeAg (47.29 ±â€¯1.86%) and HBsAg (33.58 ±â€¯0.72%) secretion after 48 h incubation, and then both decreased. In contrast, HBeAg secretion inhibition by CSSO/DrzBC and HBsAg secretion inhibition by CSSO/DrzBS were up to 73.86 ±â€¯1.77% and 67.80 ±â€¯2.51% at 48 h, and further increased to 83.83 ±â€¯2.34% and 76.79 ±â€¯2.18% at 72 h, respectively. CSSO is a promising redox-responsive polymeric carrier for efficient anti-Hepatitis B Virus gene therapy.


Assuntos
Aminas/administração & dosagem , Quitosana/administração & dosagem , Terapia Genética/métodos , Vírus da Hepatite B/efeitos dos fármacos , Oligossacarídeos/administração & dosagem , Polímeros/administração & dosagem , Aminas/metabolismo , Quitosana/metabolismo , DNA Viral/efeitos dos fármacos , DNA Viral/genética , DNA Viral/metabolismo , Relação Dose-Resposta a Droga , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/metabolismo , Células Hep G2 , Vírus da Hepatite B/genética , Vírus da Hepatite B/metabolismo , Humanos , Oligossacarídeos/metabolismo , Oxirredução/efeitos dos fármacos , Polímeros/metabolismo
12.
Theranostics ; 9(3): 691-707, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30809302

RESUMO

Responsive drug release in tumor mitochondria is a pre-requisite for mitochondria-targeted drug delivery systems to improve the efficacy of this promising therapeutic modality. To this end, a photothermal stimulation strategy for mitochondria-responsive drug release along with heat shock is developed to maximize the antitumor effects with minimal side effects. Methods: This strategy relies on mitochondrial-targeted delivery of doxorubicin (DOX) through a photothermal and lipophilic agent IR-780 iodide (IR780)-modified glycolipid conjugates (CSOSA), which can synergistically triggers high-level reactive oxygen species (ROS) to kill tumor cells. Results: Specifically, upon laser irradiation, the photothermal conversion by IR780-CSOSA can not only weaken the hydrophobic interaction between the core of micelles and DOX and trigger unexpected micelle swelling to release DOX in mitochondria for the amplification of ROS, but also induce mitochondria-specific heat shock to promote the fast evolution of ROS at the same locus to eradicate cancer cells in a more effective way. Furthermore, IR780-CSOSA micelles may independently realize the real-time diagnosis and imaging on multiple tumor models. Deep penetration into tumors by IR780-CSOSA/DOX micelles can be manipulated under laser irradiation. Conclusion: Such multifunctional IR780-CSOSA/DOX micelles with integration of mitochondria-responsive drug release and heat shock are demonstrated to be superior to the non-mitochondria-responsive therapy. This study opens up new avenues for the future cancer diagnosis and treatment.


Assuntos
Antibióticos Antineoplásicos/administração & dosagem , Doxorrubicina/administração & dosagem , Liberação Controlada de Fármacos , Resposta ao Choque Térmico , Indóis/uso terapêutico , Mitocôndrias/efeitos dos fármacos , Fototerapia , Animais , Antibióticos Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Doxorrubicina/uso terapêutico , Feminino , Glicolipídeos/administração & dosagem , Glicolipídeos/uso terapêutico , Humanos , Indóis/administração & dosagem , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Micelas , Espécies Reativas de Oxigênio/metabolismo
13.
Mater Sci Eng C Mater Biol Appl ; 97: 753-759, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30678964

RESUMO

Hepatitis c virus (HCV) infection is one of major causes for chronic liver diseases worldwide and could lead to death. Development of effective HCV vaccines is a powerful auxiliary method of existing treatments. Adjuvants are necessary for modern vaccines to promote immune responses. Among the various nanomaterials that have been developed, multihydroxylated fullerene (C60(OH)22) has been proved as an efficient adjuvant for human immunodeficiency virus DNA vaccine. Here, we utilized three types of HCV recombinant proteins as antigens to investigate the activity of C60(OH)22 as a protein vaccine adjuvant. The proteins were carried by C60(OH)22 in a way of surface adsorption and self-assemble encapsulation. C60(OH)22 at a relatively low dose was sufficient to promote both humoral and cellular immune responses to HCV protein antigens and reduce the usage of antigen. These results demonstrated the positive adjuvant properties of C60(OH)22 when applied to protein vaccines.


Assuntos
Hepacivirus/metabolismo , Hepatite C/prevenção & controle , Imunidade Celular , Imunidade Humoral , Nanopartículas/química , Proteínas Recombinantes/imunologia , Adjuvantes Imunológicos , Animais , Anticorpos Antivirais/sangue , Linfócitos B/citologia , Linfócitos B/metabolismo , Fulerenos/química , Hepatite C/imunologia , Hepatite C/patologia , Interferon gama/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/química , Linfócitos T/citologia , Linfócitos T/metabolismo , Proteínas Virais/genética , Proteínas Virais/imunologia , Proteínas Virais/metabolismo
14.
ACS Appl Mater Interfaces ; 10(39): 33532-33544, 2018 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-30192498

RESUMO

Cellular immunity is essential for the effectiveness of vaccines against cancer. After capture of vaccines, dendritic cells (DCs) have to migrate to lymph nodes via chemokine receptor type 7 (CCR7). Subsequently, DCs present cytosolic antigens via major histocompatibility complex class I (MHC I) molecules to induce cellular immunity. However, various vaccines fail to induce potent cellular immunity due to insufficient MHC I-restricted antigen presentation and limitations of immune adjuvants. Hence, we constructed novel immune adjuvant targeting micelles (M-COSA) to targeted codeliver antigen ovalbumin (OVA) and plasmid DNA encoding CCR7 (CCR7 pDNA) to the cytosol of DCs, thus promoting DC migration to lymph nodes to boost MHC I-restricted antigen presentation. M-COSA exhibited adjuvant activity and demonstrated more efficient DC cellular uptake compared with COSA. M-COSA/OVA/pDNA increased costimulatory molecule expression and cytokine secretion, resulting in DC activation and maturation. Moreover, antigens and pDNA, which were encapsulated in micelles, escaped from the endosome into the cytoplasm to achieve MHC I-restricted antigen presentation and increase CCR7 expression. The number of CD8+ T cells, which was positively correlated with tumor rejection, was notably increased and tumor growth was dramatically suppressed after vaccination with M-COSA/OVA/pDNA. In summary, M-COSA/OVA/pDNA micelles, which allow DC targeting and efficient DC migration to lymph nodes to enhance cellular immunity, exhibit effective tumor inhibition and lay the foundation for novel vaccine design.


Assuntos
Células Dendríticas/citologia , Imunidade Celular/fisiologia , Linfonodos/citologia , Micelas , Adjuvantes Imunológicos , Animais , Apresentação do Antígeno/imunologia , Linhagem Celular , Movimento Celular/fisiologia , Eletroforese em Gel de Ágar , Feminino , Imunidade Celular/genética , Interferon gama/metabolismo , Espectroscopia de Ressonância Magnética , Camundongos , Camundongos Endogâmicos C57BL , Ovalbumina/imunologia
15.
Mol Pharm ; 15(11): 5374-5386, 2018 11 05.
Artigo em Inglês | MEDLINE | ID: mdl-30204446

RESUMO

The critical process and step in achieving effective antitumor therapies is facilitating endosomal escape, which can enhance the intracellular target delivery of therapeutics. However, the normally adopted approaches tend to result in colloidal instability as a result of the inevitable interactions between the resulting positively charged surfaces of micelles and proteins in vivo. Herein, negatively charged surface shielded polymeric micelles, consisting of polymethylacrylamide derivatives and hydrophilic chitosan ( Mw = 18.8 kDa) linked by 3,3'-dithiodipropionic, are constructed. Until the pH decreases to less than 4.5, the DOX-loaded polymeric micelles (CSO-SS-PDPA/DOX) retain a negative surface charge as a result of the abundant amide groups, which could resist formation of the protein "corona" as visualized by transmission electron microscopy. Robust endosomal escape within tens of minutes due to protonated amine groups and specific redox-responsive drug release is visualized by confocal microscopy. The superior therapeutic efficacy in both 3D tumor spheroids and MCF-7 bearing mice further suggested that the prepared CSO-SS-PDPA/DOX is a promising approach for maintaining colloidal stability while achieving intracellular endosomal/lysosomal escape, which opens new opportunities for drug delivery.


Assuntos
Antibióticos Antineoplásicos/administração & dosagem , Doxorrubicina/administração & dosagem , Portadores de Fármacos/química , Neoplasias/tratamento farmacológico , Animais , Antibióticos Antineoplásicos/farmacocinética , Compostos de Bifenilo/química , Quitosana , Coloides , Doxorrubicina/farmacocinética , Liberação Controlada de Fármacos , Endossomos/metabolismo , Feminino , Humanos , Lisossomos/metabolismo , Células MCF-7 , Camundongos , Camundongos Endogâmicos BALB C , Micelas , Neoplasias/patologia , Coroa de Proteína/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
16.
Tuberculosis (Edinb) ; 111: 45-53, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-30029914

RESUMO

OBJECTIVE: We aimed to determine whether IP-10 and RANTES plasma levels can be used in diagnosis and monitoring of pulmonary tuberculosis (PTB). METHODS: Plasma levels of cytokines/chemokines were measured using a Bio-Plex® multiplex cytokine assay system in a cohort containing 457 clinically suspected PTB patients including a training set (n = 41)and two independent test sets A (n = 242) and B (n = 174). RESULTS: Plasma levels of IP-10 and RANTES were significantly higher in PTB patients than healthy controls' in both training and independent test sets (P < 0.05). Compared with other combinations, the combination of IP-10 and RANTES had the best performance with an AUC of 1.0 in training set. The performance characteristic of this model was successfully validated in independent test set A although this combination only resulted in a slightly improvement of AUC value in independent test set B. Plasma IP-10 and RANTES levels were weakly and positively correlated with blood glucose concentrations. Moreover, IP-10 levels were positively correlated with CRP and ESR in PTB patients. Furthermore, in response to therapy, both IP-10 and RANTES levels significantly decreased over the period of 6 months (P < 0.001). CONCLUSIONS: Taken together, combination of IP-10 and RANTES could be potentially used as diagnostic and monitoring biomarker in PTB management.


Assuntos
Quimiocina CCL5/sangue , Quimiocina CXCL10/sangue , Tuberculose Pulmonar/sangue , Tuberculose Pulmonar/diagnóstico , Adolescente , Adulto , Idoso , Antituberculosos/uso terapêutico , Biomarcadores/sangue , Estudos de Casos e Controles , Monitoramento de Medicamentos/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Reprodutibilidade dos Testes , Resultado do Tratamento , Tuberculose Pulmonar/tratamento farmacológico , Tuberculose Pulmonar/microbiologia , Regulação para Cima , Adulto Jovem
17.
Int J Biol Sci ; 14(4): 461-470, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29725267

RESUMO

Human vasorin (VASN) as a type I transmembrane protein, is a potential biomarker of hepatocellular carcinoma, which could expedite HepG2 cell proliferation and migration significantly in vitro. The ectodomain of VASN was proteolytically released to generate soluble VASN (sVASN), which was validated to be the active form. Among several monoclonal antibodies produced against sVASN, the clone V21 was found to bind with the recombinant human sVASN (rhsVASN) with the highest affinity and specificity, and also have inhibitory effects on proliferation and migration of HepG2 cells. Hence the phage-displayed peptide library was screened against the antibody V21. The positive phage clones were isolated and sequenced, and one unique consensus motifs was obtained. The result of sequence alignment showed that the conserved motif had similarity to VASN(Cys432-Cys441), embedded in the epidermal growth factor (EGF)-like domain. The synthetic mimotope peptide V21P1 and V21P2 were confirmed to bind with V21 and could compete with rhsVASN in ELISA assay. And they could also almost completely reverse the inhibitory effect of V21 on HepG2 migration and proliferation. Furthermore, the antibodies produced against V21P1 were able to bind not only with the peptide V21P1, but also with rhsVASN and the natural VASN from HepG2 cell. Our results showed that V21 seemed to be a functional antibody. The mimotopes toward V21 might mimic the functional domain of VASN, which would be helpful to exploit VASN functions and act as a candidate target for developing therapeutic antibodies against VASN.


Assuntos
Proteínas de Transporte/fisiologia , Proteínas de Membrana/fisiologia , Sequência de Aminoácidos , Anticorpos Monoclonais , Sítios de Ligação , Ligação Competitiva , Proteínas de Transporte/química , Proteínas de Transporte/metabolismo , Movimento Celular/genética , Proliferação de Células/genética , Clonagem Molecular , Sequência Conservada , Ensaio de Imunoadsorção Enzimática , Células Hep G2 , Humanos , Proteínas de Membrana/química , Proteínas de Membrana/metabolismo , Domínios Proteicos , Alinhamento de Sequência
18.
Biomaterials ; 161: 33-46, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29421561

RESUMO

Cancer associated fibroblasts (CAFs) are the most abundant, genetically stable stroma cells and localize near blood vessels within "finger-like" collagen-rich stroma, which lead to restrained drug transport in dense stroma instead of tumor cells inside tumor mass, especially for targeting micelles. Meanwhile, the bioactive cytokines secreted by stroma cells result in microenvironment mediated drug resistance (TMDR). Hence, a biologically inspired Telmisartan (Tel) grafting glycolipid micelles (Tel-CSOSA) are constructed, which can sequentially target angiotensin II type I receptor (AT1R) overexpressed on both CAFs and tumor cells. More Tel-CSOSA are demonstrated to specifically accumulate in tumor site compared to CSOSA. In addition, the retention of Tel-CSOSA is primarily prolonged around tumor vessel in virtue of CAFs targeting and the stroma barrier. In contrast, the elimination of "finger-like" ECM resulting from CAFs apoptosis by Tel-CSOSA/DOX contributes to a more uniform and deeper penetration post-administration, which can enforce subsequently tumor cells targeting. Meanwhile, cytokines are decreased along with CAFs apoptosis so that tumor cells are more vulnerable to chemotherapeutics. Collectively, this strategy of sequentially targeting CAFs and tumor cells could synergistically increase antitumor therapy with reversed TMDR.


Assuntos
Micelas , Receptor Tipo 1 de Angiotensina/metabolismo , Animais , Linhagem Celular Tumoral , Quitosana/metabolismo , Feminino , Fibroblastos/metabolismo , Fibroblastos/fisiologia , Glicolipídeos/química , Células Endoteliais da Veia Umbilical Humana , Humanos , Células MCF-7 , Camundongos , Camundongos Nus , Microscopia Confocal , Microscopia de Fluorescência , Células NIH 3T3 , Receptor Tipo 1 de Angiotensina/genética , Microambiente Tumoral/fisiologia , Ensaios Antitumorais Modelo de Xenoenxerto
19.
Drug Deliv ; 25(1): 341-352, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29355035

RESUMO

Metastasis is one of the major obstacles for successful therapy of breast tumor. To inhibit the metastasis and growth of breast tumor simultaneously, a Celastrol (Cela) loaded glucolipid-like conjugates (CSOSA/Cela) with αvß3-ligand Tetraiodothyroacetic acid (TET) modification (TET-CSOSA/Cela) were established to block nuclear factor-kappa B (NF-κB) signaling pathway. The distribution of TET-CSOSA was remarkably increased in lung metastasis and primary tumor of 4T1 tumor-bearing mice by means of αvß3 receptor-mediated interaction. The results demonstrated that TET-CSOSA/Cela significantly suppressed Bcl-2 activation of lung metastatic cells and reduced MMP-9 expression of 4T1 breast tumor cells by blocking NF-κB. The inhibitory rates of TET-CSOSA/Cela against lung metastasis and primary tumor were raised to 90.72 and 81.15%, compared to those of Celastrol (72.15 and 46.40%), respectively. All results demonstrated the αvß3 receptor targeted TET-CSOSA/Cela micelles exhibited great potential in treating lung metastasis and primary tumor simultaneously via blocking NF-κB signaling pathway.


Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , NF-kappa B/metabolismo , Transdução de Sinais/efeitos dos fármacos , Triterpenos/farmacologia , Animais , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Feminino , Humanos , Integrina alfaVbeta3/metabolismo , Neoplasias Pulmonares/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Micelas , Metástase Neoplásica/tratamento farmacológico , Tiroxina/análogos & derivados , Tiroxina/farmacologia
20.
Biomaterials ; 154: 169-181, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29128845

RESUMO

Mitochondria, crucial regulators of inducing tumor cells apoptosis, can be treated as the prime target for tumor therapy. The selective and responsive release of proapoptotic therapeutics into mitochondria may notably improve antitumor efficiency. Herein, (4-Carboxybutyl) triphenylphosphonium bromide (CTPP), a lipophilic cation, was conjugated with glucolipid-like conjugates (CSOSA) to produce mitochondria-targeted conjugates (CTPP-CSOSA). Loading with weakly acidic drug Celastrol (Cela), CTPP-CSOSA/Cela micelles could selectively respond to mitochondrial alkaline pH (pH 8.0), controlled by the weaker interaction between hydrophobic core of micelles and Cela with higher solubility at pH 8.0. However, there was a slow drug release behavior at pH 7.4 and pH 5.0. It illustrated that CTPP-CSOSA/Cela could realize mitochondrial fast drug release, and decrease drug leakage in the cytoplasm and lysosome. CTPP-CSOSA/Cela highly enhanced ROS levels, which further induced mitochondria membrane potential decreasing and more Cytochrome C releasing into cytoplasm, then promoted tumor cells apoptosis notably. In vivo, CTPP-CSOSA had an enhanced accumulation in tumor tissue, compared with CSOSA. Moreover, the tumor-inhibition rate of CTPP-CSOSA/Cela was 80.17%, which was significantly higher than CSOSA/Cela (58.35%) and Cela (54.89%). Thus, CTPP-CSOSA/Cela micelles with mitochondrial targeting and alkaline pH-responsive release capability could provide a new strategy for tumor therapy.


Assuntos
Liberação Controlada de Fármacos , Glicolipídeos/química , Micelas , Mitocôndrias/metabolismo , Neoplasias/tratamento farmacológico , Triterpenos/uso terapêutico , Animais , Apoptose/efeitos dos fármacos , Morte Celular , Linhagem Celular Tumoral , Sistemas de Liberação de Medicamentos , Concentração de Íons de Hidrogênio , Camundongos Nus , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/ultraestrutura , Neoplasias/patologia , Oniocompostos/química , Compostos Organofosforados/química , Tamanho da Partícula , Transdução de Sinais/efeitos dos fármacos , Eletricidade Estática , Fatores de Tempo , Distribuição Tecidual/efeitos dos fármacos , Triterpenos/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
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