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1.
Molecules ; 26(16)2021 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-34443542

RESUMO

Biofilm infections are a global public health threat, necessitating new treatment strategies. Biofilm formation also contributes to the development and spread of multidrug-resistant (MDR) bacterial strains. Biofilm-associated chronic infections typically involve colonization by more than one bacterial species. The co-existence of multiple species of bacteria in biofilms exacerbates therapeutic challenges and can render traditional antibiotics ineffective. Polymeric nanoparticles offer alternative antimicrobial approaches to antibiotics, owing to their tunable physico-chemical properties. Here, we report the efficacy of poly(oxanorborneneimide) (PONI)-based antimicrobial polymeric nanoparticles (PNPs) against multi-species bacterial biofilms. PNPs showed good dual-species biofilm penetration profiles as confirmed by confocal laser scanning microscopy. Broad-spectrum antimicrobial activity was observed, with reduction in both bacterial viability and overall biofilm mass. Further, PNPs displayed minimal fibroblast toxicity and high antimicrobial activity in an in vitro co-culture model comprising fibroblast cells and dual-species biofilms of Escherichia coli and Pseudomonas aeruginosa. This study highlights a potential clinical application of the presented polymeric platform.


Assuntos
Bactérias/metabolismo , Biofilmes/efeitos dos fármacos , Nanopartículas/química , Polímeros/farmacologia , Células 3T3 , Animais , Biomassa , Sobrevivência Celular/efeitos dos fármacos , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Camundongos , Testes de Sensibilidade Microbiana , Viabilidade Microbiana/efeitos dos fármacos , Polímeros/síntese química , Polímeros/química
2.
Molecules ; 26(16)2021 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-34443480

RESUMO

Within this study, new materials were synthesized and characterized based on polysiloxane modified with different ratios of N-acetyl-l-cysteine (NAC) and crosslinked via UV-assisted thiol-ene addition, in order to obtain efficient membranes able to resist bacterial adherence and biofilm formation. These membranes were subjected to in vitro testing for microbial adherence against S. pneumoniae using standardized tests. WISTAR rats were implanted for 4 weeks with crosslinked siloxane samples without and with NAC. A set of physical characterization methods was employed to assess the chemical structure and morphological aspects of the new synthetized materials before and after contact with the microbiological medium.


Assuntos
Antibacterianos/química , Materiais Revestidos Biocompatíveis/química , Implantes Cocleares/microbiologia , Otite/tratamento farmacológico , Polímeros/química , Siloxanas/química , Acetilcisteína/química , Acetilcisteína/farmacologia , Acetilcisteína/uso terapêutico , Animais , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Aderência Bacteriana/efeitos dos fármacos , Biofilmes/efeitos dos fármacos , Materiais Revestidos Biocompatíveis/farmacologia , Materiais Revestidos Biocompatíveis/uso terapêutico , Implantes Cocleares/efeitos adversos , Polímeros/farmacologia , Polímeros/uso terapêutico , Ratos Wistar , Siloxanas/farmacologia , Siloxanas/uso terapêutico , Streptococcus pneumoniae/efeitos dos fármacos , Compostos de Sulfidrila/química , Propriedades de Superfície
3.
Int J Mol Sci ; 22(14)2021 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-34299098

RESUMO

BACKGROUND: This study was designed to investigate the effect of cluster differentiation (CD)39 and CD73 inhibitors on the expresion of tumour-associated macrophages (TAMs), M1- versus M2-tumour phenotypes in mice with colon cancer. METHODS: An in vivo study of co-culture with colon cancer cells and immune cells from the bone marrow (BM) of mice was performed. After the confirmation of the effect of polyoxotungstate (POM-1) as an inhibitor of CD39 on TAMs, the mice were randomly divided into a control group without POM-1 and a study group with POM-1, respectively, after subcutaneous injection of CT26 cells. On day 14 after the injection, the mice were sacrificed, and TAMs were evaluated using fluorescence-activated cell sorting. RESULTS: In the in vivo study, the co-culture with POM-1 significantly increased the apoptosis of CT26 cells. The cell population from the co-culture with POM-1 showed significant increases in the expression of CD11b+ for myeloid cells, lymphocyte antigen 6 complex, locus C (Ly6C+) for monocytes, M1-tumour phenotypes from TAMs, and F4/80+ for macrophages. In the in vivo study, tumour growth in the study group with POM-1 was significantly limited, compared with the control group without POM-1. The expressions of Ly6C+ and major histocompatibility complex class II+ for M1-tumour phenotypes from TAMs on F4/80+ from the tumour tissue in the study group had significantly higher values compared with the control group. CONCLUSION: The inhibition of CD39 with POM-1 prevented the growth of colon cancer in mice, and it was associated with the increased expression of M1-tumour phenotypes from TAMs in the cancer tissue.


Assuntos
Apirase/antagonistas & inibidores , Neoplasias do Colo/prevenção & controle , Polímeros/farmacologia , Macrófagos Associados a Tumor/efeitos dos fármacos , Compostos de Tungstênio/farmacologia , Animais , Antígenos CD , Apoptose , Proliferação de Células , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Prognóstico , Células Tumorais Cultivadas , Macrófagos Associados a Tumor/metabolismo , Macrófagos Associados a Tumor/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
4.
Int J Mol Sci ; 22(14)2021 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-34299358

RESUMO

In vitro cytotoxicity of polymer-carriers, which in the side chains contain the cholinum ionic liquid units with chloride (Cl) or pharmaceutical anions dedicated for antituberculosis therapy, i.e., p-aminosalicylate (PAS) and clavulanate (CLV), was investigated. The carriers and drug conjugates were examined, in the concentration range of 3.125-100 µg/mL, against human bronchial epithelial cells (BEAS-2B) and adenocarcinomic human alveolar basal epithelial cells (A549) as an experimental model cancer cell line possibly coexisting in tuberculosis. The cytotoxicity was evaluated by MTT test and confluency index, as well as by the cytometric analyses, including Annexin-V FITC apoptosis assay. The polymer systems showed supporting activity towards the normal cells and no tumor progress, especially at the highest concentration (100 µg/mL). The analysis of cell death did not show meaningful changes in the case of the BEAS-2B, whereas in the A549 cell line, the cytostatic activity was observed, especially for the drug-free carriers, causing death in up to 80% of cells. This can be regulated by the polymer structure, including the content of cationic units, side-chain length and density, as well as the type and content of pharmaceutical anions. The results of MTT tests, confluency, as well as cytometric analyses, distinguished the polymer systems with Cl/PAS/CLV containing 26% of grafting degree and 43% of ionic units or 46% of grafting degree and 18% of ionic units as the optimal systems.


Assuntos
Citotoxinas/farmacologia , Portadores de Fármacos/farmacologia , Líquidos Iônicos/farmacologia , Polímeros/farmacologia , Células A549 , Apoptose/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Linhagem Celular , Linhagem Celular Tumoral , Citostáticos/farmacocinética , Células Epiteliais/efeitos dos fármacos , Humanos , Pulmão/efeitos dos fármacos , Mucosa Respiratória/efeitos dos fármacos
5.
Int J Mol Sci ; 22(14)2021 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-34298943

RESUMO

Graphene oxide (GO) is a biocompatible material considered a favorable stem cell culture substrate. In this study, GO was modified with polydopamine (PDA) to facilitate depositing GO onto a tissue culture polystyrene (PT) surface, and the osteogenic performance of the PDA/GO composite in pluripotent embryonic stem cells (ESCs) was investigated. The surface chemistry of the PDA/GO-coated PT surface was analyzed by scanning electron microscopy (SEM) and X-ray photoelectron spectroscopy (XPS). A high cell viability of ESCs cultured on the PDA/GO composite-coated surface was initially ensured. Then, the osteogenic differentiation of the ESCs in response to the PDA/GO substrate was assessed by alkaline phosphatase (ALP) activity, intracellular calcium levels, matrix mineralization assay, and evaluation of the mRNA and protein levels of osteogenic factors. The culture of ESCs on the PDA/GO substrate presented higher osteogenic potency than that on the uncoated control surface. ESCs cultured on the PDA/GO substrate expressed significantly higher levels of integrin α5 and ß1, as well as bone morphogenetic protein receptor (BMPR) types I and II, compared with the control groups. The phosphorylation of extracellular signal-regulated kinase (ERK)1/2, p38, and c-Jun-N-terminal kinase (JNK) mitogen-activated protein kinases (MAPKs) was observed in ESCs culture on the PDA/GO substrate. Moreover, BMP signal transduction by SMAD1/5/8 phosphorylation was increased more in cells on PDA/GO than in the control. The nuclear translocation of SMAD1/5/8 in cells was also processed in response to the PDA/GO substrate. Blocking activation of the integrin α5/ß1, MAPK, or SMAD signaling pathways downregulated the PDA/GO-induced osteogenic differentiation of ESCs. These results suggest that the PDA/GO composite stimulates the osteogenic differentiation of ESCs via the integrin α5/ß1, MAPK, and BMPR/SMAD signaling pathways.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Grafite/farmacologia , Indóis/farmacologia , Células-Tronco Embrionárias Murinas/efeitos dos fármacos , Osteogênese/efeitos dos fármacos , Polímeros/farmacologia , Animais , Técnicas de Cultura de Células , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos , Células-Tronco Embrionárias Murinas/metabolismo , Transdução de Sinais/efeitos dos fármacos
6.
J Biol Chem ; 297(2): 100940, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34237302

RESUMO

The severe acute respiratory syndrome coronavirus 2 envelope protein (S2-E) is a conserved membrane protein that is important for coronavirus (CoV) assembly and budding. Here, we describe the recombinant expression and purification of S2-E in amphipol-class amphipathic polymer solutions, which solubilize and stabilize membrane proteins, but do not disrupt membranes. We found that amphipol delivery of S2-E to preformed planar bilayers results in spontaneous membrane integration and formation of viroporin cation channels. Amphipol delivery of the S2-E protein to human cells results in plasma membrane integration, followed by retrograde trafficking to the trans-Golgi network and accumulation in swollen perinuclear lysosomal-associated membrane protein 1-positive vesicles, likely lysosomes. CoV envelope proteins have previously been proposed to manipulate the luminal pH of the trans-Golgi network, which serves as an accumulation station for progeny CoV particles prior to cellular egress via lysosomes. Delivery of S2-E to cells will enable chemical biological approaches for future studies of severe acute respiratory syndrome coronavirus 2 pathogenesis and possibly even development of "Trojan horse" antiviral therapies. Finally, this work also establishes a paradigm for amphipol-mediated delivery of membrane proteins to cells.


Assuntos
Membrana Celular/efeitos dos fármacos , Proteínas do Envelope de Coronavírus/metabolismo , Polímeros/farmacologia , Propilaminas/farmacologia , Tensoativos/farmacologia , Rede trans-Golgi/metabolismo , Membrana Celular/metabolismo , Proteínas do Envelope de Coronavírus/genética , Células HeLa , Humanos , Bicamadas Lipídicas/química , Bicamadas Lipídicas/metabolismo , Lisossomos/metabolismo , Polímeros/química , Propilaminas/química , Transporte Proteico , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Tensoativos/química
7.
Int J Mol Sci ; 22(13)2021 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-34209789

RESUMO

Near-physiological in vitro thrombogenicity test systems for the evaluation of blood-contacting endothelialized biomaterials requires co-cultivation with platelets (PLT). However, the addition of PLT has led to unphysiological endothelial cell (EC) detachment in such in vitro systems. A possible cause for this phenomenon may be PLT activation triggered by the applied endothelial cell medium, which typically consists of basal medium (BM) and nine different supplements. To verify this hypothesis, the influence of BM and its supplements was systematically analyzed regarding PLT responses. For this, human platelet rich plasma (PRP) was mixed with BM, BM containing one of nine supplements, or with BM containing all supplements together. PLT adherence analysis was carried out in six-channel slides with plasma-treated cyclic olefin copolymer (COC) and poly(tetrafluoro ethylene) (PTFE, as a positive control) substrates as part of the six-channel slides in the absence of EC and under static conditions. PLT activation and aggregation were analyzed using light transmission aggregometry and flow cytometry (CD62P). Medium supplements had no effect on PLT activation and aggregation. In contrast, supplements differentially affected PLT adherence, however, in a polymer- and donor-dependent manner. Thus, the use of standard endothelial growth medium (BM + all supplements) maintains functionality of PLT under EC compatible conditions without masking the differences of PLT adherence on different polymeric substrates. These findings are important prerequisites for the establishment of a near-physiological in vitro thrombogenicity test system assessing polymer-based cardiovascular implant materials in contact with EC and PLT.


Assuntos
Materiais Biocompatíveis/farmacologia , Plaquetas/efeitos dos fármacos , Plaquetas/fisiologia , Meios de Cultura/farmacologia , Adulto , Materiais Biocompatíveis/química , Plaquetas/citologia , Meios de Cultura/química , Endotélio/citologia , Feminino , Humanos , Masculino , Teste de Materiais , Pessoa de Meia-Idade , Ativação Plaquetária/efeitos dos fármacos , Adesividade Plaquetária/efeitos dos fármacos , Agregação Plaquetária/efeitos dos fármacos , Polímeros/farmacologia , Tecidos Suporte/química
8.
Int J Mol Sci ; 22(11)2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-34206141

RESUMO

The interaction of multi-LacNAc (Galß1-4GlcNAc)-containing N-(2-hydroxypropyl) methacrylamide (HPMA) copolymers with human galectin-1 (Gal-1) and the carbohydrate recognition domain (CRD) of human galectin-3 (Gal-3) was analyzed using NMR methods in addition to cryo-electron-microscopy and dynamic light scattering (DLS) experiments. The interaction with individual LacNAc-containing components of the polymer was studied for comparison purposes. For Gal-3 CRD, the NMR data suggest a canonical interaction of the individual small-molecule bi- and trivalent ligands with the lectin binding site and better affinity for the trivalent arrangement due to statistical effects. For the glycopolymers, the interaction was stronger, although no evidence for forming a large supramolecule was obtained. In contrast, for Gal-1, the results indicate the formation of large cross-linked supramolecules in the presence of multivalent LacNAc entities for both the individual building blocks and the polymers. Interestingly, the bivalent and trivalent presentation of LacNAc in the polymer did not produce such an increase, indicating that the multivalency provided by the polymer is sufficient for triggering an efficient binding between the glycopolymer and Gal-1. This hypothesis was further demonstrated by electron microscopy and DLS methods.


Assuntos
Proteínas Sanguíneas/química , Galectina 1/química , Galectinas/química , Metacrilatos/química , Polímeros/química , Acrilamidas/química , Acrilamidas/farmacologia , Sítios de Ligação/efeitos dos fármacos , Proteínas Sanguíneas/genética , Carboidratos/química , Microscopia Crioeletrônica , Galectina 1/genética , Galectinas/genética , Humanos , Ligantes , Metacrilatos/farmacologia , Polímeros/farmacologia , Ligação Proteica/efeitos dos fármacos
9.
J Interv Cardiol ; 2021: 2629393, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34113221

RESUMO

Objectives: To assess the impact of different guidewires on stent coating integrity in jailed wire technique (JWT) for bifurcation treatment. Background: JWT is commonly adopted to protect side branch in provisional one-stent strategy for coronary bifurcation lesions. However, this technique may cause defects in stent coatings. The degree of coating damage caused by different types of jailed wires remains unknown. Methods: A fluid model with a bifurcation was established to mimic the condition in vivo. One-stent strategy was performed with three types of guidewire (nonpolymer-jacketed wire, intermediate polymer-jacketed wire, and full polymer-jacketed wire) tested for JWT. Scanning electron microscopy (SEM) was used to evaluate stent coating integrity and wire structure. The degrees of coating defects were recorded as no, slight, moderate, and severe defects. Results: A total of 27 samples were tested. Analyses of SEM images showed a significant difference in the degree of coating damage among the three types of wire after the procedure of JWT (P < 0.001). Nonpolymer-jacketed wire could inevitably cause a severe defect in stent coatings, while full polymer-jacketed wire caused the least coating damages. Besides, there were varying degrees of coil deformation in nonpolymer-jacketed wires, while no surface damage or jacket shearing was observed in full polymer-jacketed wires. Conclusions: Although nonpolymer-jacketed wire has long been recommended for JWT, our bench-side study suggests that full polymer-jacketed wire may be a better choice. Further clinical studies are needed to confirm our findings.


Assuntos
Intervenção Coronária Percutânea/instrumentação , Ajuste de Prótese , Stents/efeitos adversos , Materiais Revestidos Biocompatíveis/farmacologia , Estenose Coronária/diagnóstico por imagem , Estenose Coronária/cirurgia , Falha de Equipamento , Humanos , Teste de Materiais/métodos , Microscopia Eletrônica de Varredura/métodos , Modelos Anatômicos , Intervenção Coronária Percutânea/métodos , Polímeros/farmacologia , Desenho de Prótese , Ajuste de Prótese/efeitos adversos , Ajuste de Prótese/métodos
10.
Adv Mater ; 33(26): e2008304, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34060150

RESUMO

Airborne pathogens pose high risks in terms of both contraction and transmission within the respiratory pathways, particularly the nasal region. However, there is little in the way of adequate intervention that can protect an individual or prevent further spread. This study reports on a nasal formulation with the capacity to combat such challenges, focusing on severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Formulation of a polysaccharide-based spray, known for its mucoadhesive properties, is undertaken and it is characterized for its mechanical, spray distribution, and antiviral properties. The ability to engineer key mechanical characteristics such as dynamic yield stresses and high coverage is shown, through systematic understanding of the composite mixture containing both gellan and λ-carrageenan. Furthermore, the spray systems demonstrate highly potent capacities to prevent SARS-CoV-2 infection in Vero cells, resulting in complete inhibition when either treating, the cells, or the virus, prior to challenging for infection. From this data, a mechanism for both prophylaxis and prevention is proposed; where entrapment within a polymeric coating sterically blocks virus uptake into the cells, inactivating the virus, and allowing clearance within the viscous medium. As such, a fully preventative spray is formulated, targeted at protecting the lining of the upper respiratory pathways against SARS-CoV-2.


Assuntos
Composição de Medicamentos , Sprays Nasais , Polímeros/química , SARS-CoV-2/fisiologia , Animais , COVID-19/patologia , COVID-19/virologia , Carragenina/química , Chlorocebus aethiops , Humanos , Polímeros/farmacologia , Polissacarídeos Bacterianos/química , SARS-CoV-2/isolamento & purificação , Células Vero , Internalização do Vírus/efeitos dos fármacos
11.
Nat Commun ; 12(1): 3961, 2021 06 25.
Artigo em Inglês | MEDLINE | ID: mdl-34172721

RESUMO

Current materials used in biomedical devices do not match tissue's mechanical properties and leach various chemicals into the body. These deficiencies pose significant health risks that are further exacerbated by invasive implantation procedures. Herein, we leverage the brush-like polymer architecture to design and administer minimally invasive injectable elastomers that cure in vivo into leachable-free implants with mechanical properties matching the surrounding tissue. This strategy allows tuning curing time from minutes to hours, which empowers a broad range of biomedical applications from rapid wound sealing to time-intensive reconstructive surgery. These injectable elastomers support in vitro cell proliferation, while also demonstrating in vivo implant integrity with a mild inflammatory response and minimal fibrotic encapsulation.


Assuntos
Materiais Biomiméticos/administração & dosagem , Elastômeros/administração & dosagem , Procedimentos Cirúrgicos Reconstrutivos/métodos , Animais , Materiais Biocompatíveis/administração & dosagem , Materiais Biocompatíveis/química , Materiais Biocompatíveis/farmacologia , Materiais Biomiméticos/química , Materiais Biomiméticos/farmacologia , Proliferação de Células/efeitos dos fármacos , Elastômeros/química , Elastômeros/farmacologia , Géis , Injeções , Camundongos , Polímeros/administração & dosagem , Polímeros/química , Polímeros/farmacologia , Ratos , Fatores de Tempo
12.
ACS Appl Mater Interfaces ; 13(24): 27955-27962, 2021 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-34124876

RESUMO

Fabricating antibacterial hydrogels with antimicrobial drugs and synthetic biocompatible biomimetic hydrogels is a promising strategy for practical medical applications. Here, we report a bicomponent hydrogel composed of a biomimetic polyisocyanopetide (PIC) hydrogel and a photodynamic antibacterial membrane-intercalating conjugated oligoelectrolyte (COE). The aggregation behavior and aggregate size of the COEs in water can be regulated using the PIC hydrogel, which could induce COEs with higher reactive oxygen species (ROS) production efficiency and increased association of COEs toward bacteria, therefore enhancing the antibacterial efficiency. This strategy provides a facile method for developing biomimetic hydrogels with high antibacterial capability.


Assuntos
Antibacterianos/farmacologia , Hidrogéis/farmacologia , Fármacos Fotossensibilizantes/farmacologia , Polímeros/farmacologia , Tiadiazóis/farmacologia , Tiofenos/farmacologia , Antibacterianos/química , Antibacterianos/efeitos da radiação , Materiais Biomiméticos/química , Materiais Biomiméticos/farmacologia , Materiais Biomiméticos/efeitos da radiação , Escherichia coli/efeitos dos fármacos , Fluoresceínas/química , Fluoresceínas/metabolismo , Corantes Fluorescentes/química , Corantes Fluorescentes/metabolismo , Hidrogéis/química , Hidrogéis/efeitos da radiação , Luz , Testes de Sensibilidade Microbiana , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/efeitos da radiação , Polímeros/química , Polímeros/efeitos da radiação , Espécies Reativas de Oxigênio/metabolismo , Staphylococcus aureus/efeitos dos fármacos , Tiadiazóis/química , Tiadiazóis/efeitos da radiação , Tiofenos/química , Tiofenos/efeitos da radiação
14.
J Mater Chem B ; 9(20): 4169-4177, 2021 05 26.
Artigo em Inglês | MEDLINE | ID: mdl-33989375

RESUMO

Bacteria associated infection is a critical challenge for metallic implants and devices in biomedical applications. Here, we report phosphonate/zwitterionic/quaternary amine terpolymers as a new type of antifouling and bactericidal coating for metallic substrates. Through reversible-addition fragmentation chain transfer polymerization (RAFT) and quaternization, well-controlled phosphonate/zwitterionic/cationic terpolymers with identical phosphonate segments (repeat units of 15) and varied zwitterionic and cationic components (nSBMA : nTMAEMA = 64 : 0, 54 : 18, 18 : 32, 9 : 52, and 0 : 70) were precisely prepared. The polymers can be coated on TC4 substrates based on the strong coordination between phosphonate groups and metallic substrates, as evidenced by water contact angle and XPS tests. Bactericidal evaluation revealed that the antibacterial efficiency was enhanced with the increase of cationic content in the coating polymers. TC4 substrates coated with the polymer coating with a cationic segment of 70 repeat units were able to kill 97.5 and 94.0% of S. aureus and E. coli, respectively. By virtue of the antifouling ability of the zwitterionic component and the bactericidal ability of the cationic component, the antibacterial efficiency was increased to 99.5% without significant compromising of the cytocompatibility. Meanwhile, the dual functional terpolymers could be easily applied on other metallic substrates, such as titanium, stainless steel, and Ni/Cr alloy, which were able to kill up to 97.9% of S. aureus and 99.9% of E. coli, respectively, endowing the excellent antibacterial properties to general bio-metals. The high-efficiency antibacterial modification strategy demonstrated here may find many applications on metallic implants and devices to combat bacterial associated infections.


Assuntos
Antibacterianos/farmacologia , Incrustação Biológica/prevenção & controle , Materiais Revestidos Biocompatíveis/farmacologia , Complexos de Coordenação/farmacologia , Organofosfonatos/farmacologia , Polímeros/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Cátions/química , Cátions/farmacologia , Materiais Revestidos Biocompatíveis/síntese química , Materiais Revestidos Biocompatíveis/química , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Escherichia coli/efeitos dos fármacos , Teste de Materiais , Testes de Sensibilidade Microbiana , Organofosfonatos/química , Polímeros/química , Staphylococcus aureus/efeitos dos fármacos
15.
J Biol Chem ; 297(1): 100806, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34022223

RESUMO

Sensing noxiously high temperatures is crucial for living organisms to avoid heat-induced injury. The TRPV1 channel has long been known as a sensor for noxious heat. However, the mechanism of how this channel is activated by heat remains elusive. Here we found that a series of polyols including sucrose, sorbitol, and hyaluronan significantly elevate the heat activation threshold temperature of TRPV1. The modulatory effects of these polyols were only observed when they were perfused extracellularly. Interestingly, mutation of residues E601 and E649 in the outer pore region of TRPV1 largely abolished the effects of these polyols. We further observed that intraplantar injection of polyols into the hind paws of rats reduced their heat-induced pain response. Our observations not only suggest that the extracellular regions of TRPV1 are critical for the modulation of heat activation by polyols, but also indicate a potential role of polyols in reducing heat-induced pain sensation.


Assuntos
Temperatura Alta , Polímeros/farmacologia , Canais de Cátion TRPV/metabolismo , Sequência de Aminoácidos , Animais , Capsaicina/farmacologia , Espaço Extracelular/química , Feminino , Células HEK293 , Humanos , Ativação do Canal Iônico/efeitos dos fármacos , Polímeros/química , Prótons , Ratos Wistar , Canais de Cátion TRPV/química
16.
ACS Biomater Sci Eng ; 7(5): 1780-1786, 2021 05 10.
Artigo em Inglês | MEDLINE | ID: mdl-33966379

RESUMO

Infections caused by multidrug-resistant (MDR) bacteria present an emerging global health crisis, and the threat is intensified by the involvement of biofilms. Some biofilm infections involve more than one species; this can further challenge treatment using traditional antibiotics. Nanomaterials are being developed as alternative therapeutics to traditional antibiotics; here we report biodegradable polymer-stabilized oil-in-water nanosponges (BNS) and show their activity against dual-species bacterial biofilms. The described engineered nanosponges demonstrated broad-spectrum antimicrobial activity through prevention of dual-species biofilm formation as well as eradication of preformed biofilms. The BNS showed no toxicity against mammalian cells. Together, these data highlight the therapeutic potential of this platform.


Assuntos
Biofilmes , Farmacorresistência Bacteriana Múltipla , Animais , Antibacterianos/farmacologia , Bactérias , Polímeros/farmacologia
17.
Chem Commun (Camb) ; 57(34): 4158-4161, 2021 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-33908477
18.
J Mater Chem B ; 9(14): 3153-3160, 2021 04 14.
Artigo em Inglês | MEDLINE | ID: mdl-33885619

RESUMO

Photothermal therapy is promising for augmenting cancer therapeutic outcomes in cancer treatment. Diketopyrrolopyrrole (DPP)-conjugated polymer nanoparticles are in focus due to their dual photoacoustic imaging and photothermal therapy functions. Herein, the design and synthesis of three near-infrared absorbing conjugated polymers, named DPP-SO, DPP-SS and DPP-SSe, with heteroatom substitution of the thiophene moiety were developed for a photoacoustic imaging guided photothermal therapy. It was demonstrated that systematically changing only the heteroatom from O to S or Se could apparently adjust the absorption spectrum and energy gap of DPP-conjugated polymers to obtain the most suitable photothermal transduction agents (PTAs) for use in biomedicine. The characterization of photophysical properties proved that the photothermal conversion efficiency and absorption coefficient of DPP-SO nanoparticles under 808 nm irradiation was up to 79.3% and 66.51 L g-1 cm-1, respectively, which were much higher than those of DPP-SS and DPP-SSe nanoparticles. Remarkably, the IC50 value of DPP-SO for killing A549 cells was half that of DPP-SS and DPP-SSe nanoparticles. Further in vivo works demonstrated efficient photothermal therapeutic effects of DPP-SO nanoparticles with the guidance of photoacoustic imaging. Thus, this is an efficient method to regulate the photothermal performance of DPP-conjugated polymers by changing the heteroatom in the molecular skeleton.


Assuntos
Antineoplásicos/farmacologia , Calcogênios/farmacologia , Cetonas/farmacologia , Nanopartículas/química , Técnicas Fotoacústicas , Terapia Fototérmica , Polímeros/farmacologia , Pirróis/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Calcogênios/química , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Cetonas/química , Camundongos , Camundongos Nus , Neoplasias Experimentais/diagnóstico por imagem , Neoplasias Experimentais/tratamento farmacológico , Polímeros/química , Pirróis/química
19.
J Mater Chem B ; 9(13): 3055-3067, 2021 04 07.
Artigo em Inglês | MEDLINE | ID: mdl-33885667

RESUMO

Drug resistance of cisplatin significantly limits its therapeutic efficacy in clinical applications against different cancers. Herein, we develop a novel strategy to overcome cisplatin drug resistance through sensitizing cisplatin-resistant human lung cancer cells (A549R) under amplified oxidative stress using a vesicular nanoreactor for simultaneous cisplatin delivery and H2O2 generation. We engineer the nanoreactor by the self-assembly of the amphiphilic diblock copolymers to co-deliver glucose oxidase (GOD) and cisplatin (Cis) (Cis/GOD@Bz-V). Cis/GOD@Bz-V was rationally designed to stay impermeable during blood circulation while mild acidity (pH 6.5-6.8) can activate its molecular-weight selective membrane permeability and release cisplatin locally. Diffusion of small molecules such as oxygen and glucose across the membranes can induce the in situ generation of superfluous H2O2 to promote cellular oxidative stress and sensitize A549R cells via activation of pro-apoptotic pathways. Cis/GOD@Bz-V nanoreactors could effectively kill A549R at pH 6.8 in the presence of glucose by the combination of H2O2 generation and cisplatin release. Growth of A549R xenograft tumors can be inhibited efficiently without the obvious toxic side effects via the systemic administration of Cis/GOD@Bz-V. Accordingly, the tumor acidity-activable cisplatin-loaded nanoreactors show great potential to enhance the therapeutic efficacy against cisplatin-resistant cancers.


Assuntos
Antineoplásicos/farmacologia , Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias Pulmonares/tratamento farmacológico , Nanotecnologia , Polímeros/farmacologia , Células A549 , Animais , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cisplatino/química , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Estrutura Molecular , Nanotecnologia/instrumentação , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Estresse Oxidativo/efeitos dos fármacos , Tamanho da Partícula , Polímeros/síntese química , Polímeros/química , Espécies Reativas de Oxigênio/análise , Espécies Reativas de Oxigênio/metabolismo
20.
J Mater Chem B ; 9(13): 3068-3078, 2021 04 07.
Artigo em Inglês | MEDLINE | ID: mdl-33885668

RESUMO

Advanced gastric cancer (GC) is a significant threat to human health. Oridonin (ORI), isolated from the Chinese herb Rabdosia rubescens, has demonstrated great potential in GC therapy. However, the application of ORI in the clinic was greatly hindered by its poor solubility, low bioavailability, and rapid plasma clearance. Herein, a simple and novel redox-sensitive ORI polymeric prodrug formulation was synthesized by covalently attaching ORI to poly(ethylene glycol)-block-poly(l-lysine) via a disulfide linker, which can self-assemble into micelles (P-ss-ORI) in aqueous solutions and produce low critical micelle concentrations (about 10 mg L-1), characterized by small size (about 80 nm), negative surface charge (about -12 mV), and high drug loading efficiency (18.7%). The in vitro drug release study showed that P-ss-ORI can rapidly and completely release ORI in a glutathione (GSH)-rich environment and under low pH conditions. Moreover, in vitro and in vivo investigations confirmed that P-ss-ORI could remarkably extend the blood circulation time of ORI, enrich in tumor tissue, be effectively endocytosed by GC cancer cells, and quickly and completely release the drug under high intracellular GSH concentrations and low pH conditions, all these characteristics ultimately inhibit the growth of GC. This redox and pH dual-responsive P-ss-ORI formulation provides a useful strategy for GC treatment.


Assuntos
Antineoplásicos/farmacologia , Diterpenos do Tipo Caurano/farmacologia , Desenho de Fármacos , Polímeros/farmacologia , Pró-Fármacos/farmacologia , Neoplasias Gástricas/tratamento farmacológico , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Diterpenos do Tipo Caurano/síntese química , Diterpenos do Tipo Caurano/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Micelas , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/patologia , Polímeros/síntese química , Polímeros/química , Pró-Fármacos/síntese química , Pró-Fármacos/química , Ratos , Ratos Sprague-Dawley , Neoplasias Gástricas/patologia , Células Tumorais Cultivadas
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