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1.
Proc Natl Acad Sci U S A ; 119(34): e2207841119, 2022 08 23.
Artigo em Inglês | MEDLINE | ID: mdl-35969778

RESUMO

The targeted delivery of messenger RNA (mRNA) to desired organs remains a great challenge for in vivo applications of mRNA technology. For mRNA vaccines, the targeted delivery to the lymph node (LN) is predicted to reduce side effects and increase the immune response. In this study, we explored an endogenously LN-targeting lipid nanoparticle (LNP) without the modification of any active targeting ligands for developing an mRNA cancer vaccine. The LNP named 113-O12B showed increased and specific expression in the LN compared with LNP formulated with ALC-0315, a synthetic lipid used in the COVID-19 vaccine Comirnaty. The targeted delivery of mRNA to the LN increased the CD8+ T cell response to the encoded full-length ovalbumin (OVA) model antigen. As a result, the protective and therapeutic effect of the OVA-encoding mRNA vaccine on the OVA-antigen-bearing B16F10 melanoma model was also improved. Moreover, 113-O12B encapsulated with TRP-2 peptide (TRP2180-188)-encoding mRNA also exhibited excellent tumor inhibition, with the complete response of 40% in the regular B16F10 tumor model when combined with anti-programmed death-1 (PD-1) therapy, revealing broad application of 113-O12B from protein to peptide antigens. All the treated mice showed long-term immune memory, hindering the occurrence of tumor metastatic nodules in the lung in the rechallenging experiments that followed. The enhanced antitumor efficacy of the LN-targeting LNP system shows great potential as a universal platform for the next generation of mRNA vaccines.


Assuntos
Vacinas Anticâncer , Nanopartículas , Neoplasias , Vacinas de mRNA , Amino Álcoois , Animais , Antígenos/metabolismo , Linfócitos T CD8-Positivos , Vacinas Anticâncer/uso terapêutico , Decanoatos , Memória Imunológica , Lipossomos , Linfonodos , Camundongos , Metástase Neoplásica/prevenção & controle , Neoplasias/terapia , Ovalbumina , Vacinas de mRNA/uso terapêutico
2.
Nano Lett ; 24(26): 8080-8088, 2024 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-38888232

RESUMO

Among various mRNA carrier systems, lipid nanoparticles (LNPs) stand out as the most clinically advanced. While current clinical trials of mRNA/LNP therapeutics mainly address liver diseases, the potential of mRNA therapy extends far beyond─yet to be unraveled. To fully unlock the promises of mRNA therapy, there is an urgent need to develop safe and effective LNP systems that can target extrahepatic organs. Here, we report on the development of sulfonium lipid nanoparticles (sLNPs) for systemic mRNA delivery to the lungs. sLNP effectively and specifically delivered mRNA to the lungs following intravenous administration in mice. No evidence of lung and systemic inflammation or toxicity in major organs was induced by sLNP. Our findings demonstrated that the newly developed lung-specific sLNP platform is both safe and efficacious. It holds great promise for advancing the development of new mRNA-based therapies for the treatment of lung-associated diseases and conditions.


Assuntos
Lipídeos , Pulmão , Nanopartículas , RNA Mensageiro , Animais , Pulmão/metabolismo , Nanopartículas/química , Camundongos , RNA Mensageiro/genética , RNA Mensageiro/administração & dosagem , Lipídeos/química , Humanos , Compostos de Sulfônio/química , Técnicas de Transferência de Genes , Lipossomos
3.
Nature ; 553(7687): 217-221, 2018 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-29258297

RESUMO

Although genetic factors contribute to almost half of all cases of deafness, treatment options for genetic deafness are limited. We developed a genome-editing approach to target a dominantly inherited form of genetic deafness. Here we show that cationic lipid-mediated in vivo delivery of Cas9-guide RNA complexes can ameliorate hearing loss in a mouse model of human genetic deafness. We designed and validated, both in vitro and in primary fibroblasts, genome editing agents that preferentially disrupt the dominant deafness-associated allele in the Tmc1 (transmembrane channel-like gene family 1) Beethoven (Bth) mouse model, even though the mutant Tmc1Bth allele differs from the wild-type allele at only a single base pair. Injection of Cas9-guide RNA-lipid complexes targeting the Tmc1Bth allele into the cochlea of neonatal Tmc1Bth/+ mice substantially reduced progressive hearing loss. We observed higher hair cell survival rates and lower auditory brainstem response thresholds in injected ears than in uninjected ears or ears injected with control complexes that targeted an unrelated gene. Enhanced acoustic startle responses were observed among injected compared to uninjected Tmc1Bth/+ mice. These findings suggest that protein-RNA complex delivery of target gene-disrupting agents in vivo is a potential strategy for the treatment of some types of autosomal-dominant hearing loss.


Assuntos
Proteínas Associadas a CRISPR/administração & dosagem , Edição de Genes/métodos , Genes Dominantes/genética , Terapia Genética/métodos , Perda Auditiva/genética , Estimulação Acústica , Alelos , Animais , Animais Recém-Nascidos , Limiar Auditivo , Sequência de Bases , Proteínas Associadas a CRISPR/metabolismo , Proteínas Associadas a CRISPR/uso terapêutico , Sistemas CRISPR-Cas , Sobrevivência Celular , Cóclea/citologia , Cóclea/metabolismo , Modelos Animais de Doenças , Potenciais Evocados Auditivos do Tronco Encefálico , Feminino , Fibroblastos , Células Ciliadas Auditivas/citologia , Perda Auditiva/fisiopatologia , Perda Auditiva/prevenção & controle , Humanos , Lipossomos , Masculino , Proteínas de Membrana/genética , Camundongos , Reflexo de Sobressalto
4.
Angew Chem Int Ed Engl ; 55(5): 1760-4, 2016 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-26694087

RESUMO

Antimicrobial resistance poses serious public health concerns and antibiotic misuse/abuse further complicates the situation; thus, it remains a considerable challenge to optimize/improve the usage of currently available drugs. We report a general strategy to construct a bacterial strain-selective delivery system for antibiotics based on responsive polymeric vesicles. In response to enzymes including penicillin G amidase (PGA) and ß-lactamase (Bla), which are closely associated with drug-resistant bacterial strains, antibiotic-loaded polymeric vesicles undergo self-immolative structural rearrangement and morphological transitions, leading to sustained release of antibiotics. Enhanced stability, reduced side effects, and bacterial strain-selective drug release were achieved. Considering that Bla is the main cause of bacterial resistance to ß-lactam antibiotic drugs, as a further validation, we demonstrate methicillin-resistant S. aureus (MRSA)-triggered release of antibiotics from Bla-degradable polymeric vesicles, in vitro inhibition of MRSA growth, and enhanced wound healing in an in vivo murine model.


Assuntos
Anti-Infecciosos/administração & dosagem , Polímeros/química , Anti-Infecciosos/farmacologia , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Microscopia Eletrônica/métodos , Espectrometria de Fluorescência
5.
Adv Sci (Weinh) ; 10(14): e2203472, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-36935373

RESUMO

Non-invasive light-based antibacterial therapy has a good prospect in non-surgical treatment of peri-implant infections. However, its applications are severely limited by poor penetration of light into human tissues, leading to unsatisfying outcomes. Moreover, as an essential prerequisite for traditional light therapy, lasers can no longer meet the patients' needs for convenient treatment at any time. To break through the spatial and temporal limitations of traditional light therapy, a wireless-powered blue-light zirconia implant for readily available treatment of peri-implant infection is proposed. In space, complete irradiation to complex peri-implant structure is realized by the built-in wireless-powered light source, thus improving the efficacy. In time, wireless-powering allows timely and controllable anti-infection treatment. Blue micro-light emitting diodes are used as therapeutic light sources, which effectively kill peri-implant infection-related bacteria without exogenous photosensitive agents. Porphyromonas gingivalis biofilm on implant surface can be completely killed after 20 min irradiation in vitro. The bactericidal rate of peri-implant methicillin-resistant Staphylococcus aureus infection reaches 99.96 ± 0.03% under 30 min per day blue light exposure in vivo. Within the scope of this study, the treatment of peri-implant infection with blue-light implant has preliminary feasibility, giving a new approach to non-invasive treatment of deep oral infections, including peri-implant infections.


Assuntos
Anti-Infecciosos , Staphylococcus aureus Resistente à Meticilina , Fotoquimioterapia , Humanos , Desinfecção/métodos , Porphyromonas gingivalis , Fotoquimioterapia/métodos , Antibacterianos
6.
Biomacromolecules ; 13(11): 3877-86, 2012 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-23013152

RESUMO

Polymeric drug nanocarriers integrated with diagnostic and sensing functions are capable of in situ monitoring the biodistribution of chemotherapeutic drugs and imaging/contrasting agents, which enables the establishment of image-guided personalized cancer therapeutic protocols. Responsive multifunctional theranostic nanocarriers possessing external stimuli-tunable drug release rates and imaging signal intensities represent another promising direction in this field. In this work, we fabricated responsive amphiphilic diblock copolymer micelles exhibiting light-triggered hydrophobic-hydrophilic transition within micellar cores and the concomitant enhancement of magnetic resonance (MR) imaging contrast performance and release rate of physically encapsulated hydrophobic drugs. POEGMA-b-P(NIPAM-co-NBA-co-Gd) diblock copolymer covalently labeled with Gd(3+) complex (Gd) in the light-responsive block was synthesized at first, where OEGMA, NIPAM, and NBA are oligo(ethylene glycol) monomethyl ether methacrylate, N-isopropylacrylamide, and o-nitrobenzyl acrylate, respectively. The amphiphilic diblock copolymer spontaneously self-assembles in aqueous solution into micellar nanoparticles possessing hydrophobic P(NIPAM-co-NBA-co-Gd) cores and hydrophilic POEGMA coronas, which can physically encapsulate doxorubicin (Dox) as a model chemotherapeutic drug. Upon UV irradiation, hydrophobic NBA moieties within micellar cores transform into hydrophilic carboxyl derivatives, triggering micelle microstructural changes and core swelling. During this process, the microenvironment surrounding Gd(3+) complexes was subjected to a transition from being hydrophobic to hydrophilic, leading to the enhancement of MR imaging contrast performance, that is, ~1.9-fold increase in longitudinal relaxivity (r(1)). In addition, the release rate of encapsulated Dox was also enhanced (~65% of Dox release in 12 h upon UV irradiation versus ~47% Dox release in 25 h for the control). The reported strategy of light-triggered coenhancement of MR imaging contrast performance and drug release profiles represents a general route to the construction of next generation smart polymeric theranostic nanocarriers.


Assuntos
Doxorrubicina/metabolismo , Portadores de Fármacos/metabolismo , Micelas , Polímeros/metabolismo , Tensoativos/metabolismo , Acrilamidas/síntese química , Antineoplásicos/administração & dosagem , Antineoplásicos/metabolismo , Linhagem Celular , Meios de Contraste/administração & dosagem , Meios de Contraste/química , Doxorrubicina/administração & dosagem , Células Hep G2 , Humanos , Interações Hidrofóbicas e Hidrofílicas , Luz , Imageamento por Ressonância Magnética , Metacrilatos/síntese química , Nanopartículas/química , Nitrobenzoatos/síntese química , Polietilenoglicóis/síntese química , Polímeros/química , Tensoativos/química , Distribuição Tecidual
7.
ChemMedChem ; 17(6): e202100678, 2022 03 18.
Artigo em Inglês | MEDLINE | ID: mdl-34890114

RESUMO

Many intracellular signaling events remain poorly characterized due to a general lack of tools to interfere with "undruggable" targets. Antibodies have the potential to elucidate intracellular mechanisms via targeted disruption of cell signaling cascades because of their ability to bind to a target with high specificity and affinity. However, due to their size and chemical composition, antibodies cannot innately cross the cell membrane, and thus access to the cytosol with these macromolecules has been limited. Herein we describe strategies for accessing the intracellular space with recombinant antibodies mediated by cationic lipid nanoparticles to selectively disrupt intracellular signaling events. Together, our results demonstrate the use of recombinantly produced antibodies, delivered at concentrations of 10 nM, to selectively interfere with signaling driven by a single posttranslational modification. Efficient intracellular delivery of engineered antibodies opens up possibilities for modulation of previously "undruggable" targets, including for potential therapeutic applications.


Assuntos
Nanopartículas , Anticorpos , Lipossomos , Nanopartículas/química , Transdução de Sinais
8.
J Control Release ; 345: 176-189, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35157939

RESUMO

Peptide- and protein-based therapeutics have drawn significant attention over the past few decades for the treatment of infectious diseases, genetic disorders, oncology, and many other clinical needs. Yet, protecting peptide- and protein-based drugs from degradation and denaturation during processing, storage and delivery remain significant challenges. In this review, we introduce the properties of peptide- and protein-based drugs and the challenges associated with their stability and delivery. Then, we discuss delivery strategies using synthetic polymers and their advantages and limitations. This is followed by a focus on silk protein-based materials for peptide/protein drug processing, storage, and delivery, as a path to overcome stability and delivery challenges with current systems.


Assuntos
Sistemas de Liberação de Medicamentos , Seda , Hidrogéis , Peptídeos , Polímeros
9.
ACS Biomater Sci Eng ; 8(2): 722-733, 2022 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-35104103

RESUMO

Chimeric antigen receptor (CAR)-engineered adoptive cell therapy marks a revolution in cancer treatment based on the highly successful responses to CAR T cell therapy in the treatment of blood cancers. Due to the versatile structure of CARs, this technology can be easily adapted to other immune cell types, including macrophages and NKs, and applied in the treatment of many other cancers. However, high costs and fatal adverse effects represent significant concerns for future development. In vitro transcribed (IVT) mRNA therapeutics, which possess a high safety profile and straightforward production methods, could provide a useful alternative for CAR cell construction. However, the low stability and transfection efficiency of IVT-mRNA in immune cells limit further applications. In this work, we successfully engineered CAR macrophages (CAR-Ms) and CAR T cells with CAR mRNA using lipid nanoparticles (LNPs). Both the LNP formulations and mRNA modifications were optimized for in vitro mRNA transfection. More importantly, the CAR macrophages and CAR T cells both demonstrated significant cytotoxic effects on B lymphoma in vitro, underscoring the great potential of mRNA-engineered adoptive cell therapy.


Assuntos
Receptores de Antígenos Quiméricos , Lipossomos , Macrófagos/metabolismo , Nanopartículas , RNA Mensageiro/química , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores de Antígenos Quiméricos/genética , Receptores de Antígenos Quiméricos/metabolismo , Linfócitos T/metabolismo
10.
ACS Nano ; 14(2): 1919-1935, 2020 02 25.
Artigo em Inglês | MEDLINE | ID: mdl-31935063

RESUMO

The utilization of enzymes as a triggering module could endow responsive polymeric nanostructures with selectivity in a site-specific manner. On the basis of the fact that endogenous NAD(P)H:quinone oxidoreductase isozyme 1 (NQO1) is overexpressed in many types of tumors, we report on the fabrication of photosensitizer-conjugated polymeric vesicles, exhibiting synergistic NQO1-triggered turn-on of both near-infrared (NIR) fluorescence emission and a photodynamic therapy (PDT) module. For vesicles self-assembled from amphiphilic block copolymers containing quinone trimethyl lock-capped self-immolative side linkages and quinone-bridged photosensitizers (coumarin and Nile blue) in the hydrophobic block, both fluorescence emission and PDT potency are initially in the "off" state due to "double quenching" effects, that is, dye-aggregation-caused quenching and quinone-rendered PET (photoinduced electron transfer) quenching. After internalization into NQO1-positive vesicles, the cytosolic NQO1 enzyme triggers self-immolative cleavage of quinone linkages and fluorogenic release of conjugated photosensitizers, leading to NIR fluorescence emission turn-on and activated PDT. This process is accompanied by the transformation of vesicles into cross-linked micelles with hydrophilic cores and smaller sizes and triggered dual drug release, which could be directly monitored by enhanced magnetic resonance (MR) imaging for vesicles conjugated with a DOTA(Gd) complex in the hydrophobic bilayer. We further demonstrate that the above strategy could be successfully applied for activated NIR fluorescence imaging and tissue-specific PDT under both cellular and in vivo conditions.


Assuntos
Antineoplásicos/farmacologia , NAD(P)H Desidrogenase (Quinona)/metabolismo , Imagem Óptica , Fotoquimioterapia , Fármacos Fotossensibilizantes/farmacologia , Polímeros/farmacologia , Células A549 , Antineoplásicos/química , Antineoplásicos/metabolismo , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cumarínicos/química , Cumarínicos/metabolismo , Cumarínicos/farmacologia , Citosol/enzimologia , Portadores de Fármacos/química , Portadores de Fármacos/metabolismo , Portadores de Fármacos/farmacologia , Liberação Controlada de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Transporte de Elétrons , Células HeLa , Humanos , Estrutura Molecular , NAD(P)H Desidrogenase (Quinona)/química , Oxazinas/química , Oxazinas/metabolismo , Oxazinas/farmacologia , Tamanho da Partícula , Processos Fotoquímicos , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/metabolismo , Polímeros/química , Polímeros/metabolismo , Propriedades de Superfície
11.
J Mater Chem B ; 8(35): 7966-7976, 2020 09 21.
Artigo em Inglês | MEDLINE | ID: mdl-32756660

RESUMO

The accumulation of skin diseases has increased the need for biomimicking materials with high bioactivity and biosafety for wound healing, where how to improve the cell affinity of the skin regenerative materials as well as their neovascularization capacity is a key factor for rapid regeneration of the injured skin tissue. In the current study, we developed an advanced type of biodegradable nanofibrous biofilm which can attract skin-related cells and accelerate blood vessel formation for skin regeneration. Firstly, bioactive nanohybrids (LEU@LP) were fabricated via in situ doping of the nutrient amino acid leucine (beneficial for fibroblast proliferation and protein synthesis) into LAPONITE® nanodisks (enriched in Mg and Si favorable for vascularization). LEU@LP nanoparticles were then hybridized with a biodegradable polylactide (PLA) nanofibrous mesh via an airbrushing technique, followed by a subsequent ammonia plasma surface treatment to improve PLA's hydrophilicity to increase cell affinity. The resulting hybrid biofilms with skin-biomimicking nanofibrous structural networks can promote cell adhesion, spreading, migration and proliferation of fibroblasts, leading to the ideal skin wound healing (with blood vessel formation and hair follicle regeneration), probably attributed to their better hydrophilicity to promote cell affinity and the capacity of sustainable release of leucine (beneficial for fibroblasts proliferation) and the composition provision (Mg and Si which are beneficial for neovascularization).


Assuntos
Materiais Biocompatíveis/química , Materiais Biocompatíveis/farmacologia , Leucina/química , Leucina/farmacologia , Neovascularização Fisiológica/efeitos dos fármacos , Regeneração/efeitos dos fármacos , Pele/efeitos dos fármacos , Animais , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Camundongos , Nanoestruturas/química , Poliésteres/química , Pele/irrigação sanguínea
12.
Acta Biomater ; 115: 160-175, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32791348

RESUMO

Absence of ligament-bone healing due to poor bioactivity and hyperplasia of fibrous tissue caused by immune response severely impairs ligament grafts' functional duration in anterior cruciate ligament (ACL) reconstruction. While osteogenic modification is a popular technique for promoting ligament-bone integration, inadequate osseointegration remains a common experience, due to occupying fibrous hyperplasia and impaired osteogenesis potential. In the present study, a triple-nano-coating polyethylene terephthalate (PET) graft was developed by polydopamine self-assembly, chondroitin sulfate (CS) chemical-grafting and BMP-2 physical-immobilization to facilitate robust ligament-bone healing, The CS/polydopamine-modified PET (C-pPET) graft was demonstrated to inhibit fibrogenesis by regulating polarization of macrophages and promoting the secretion of anti-inflammatory factors. Moreover, the immunoregulatory function of CS cooperated with BMP-2 to facilitate osteogenic differentiation of stem cells, promoting the expression of ALP, Runx2, OCN and COL I. Bone regeneration was significantly enhanced at early-middle stage in the BMP-loaded pPET (B/pPET) group, while occurring at middle-late stage in the C-pPET group. Continuous new bone formation and optimal ligament-bone healing were observed in the B/C-pPET group via sequential and synergistic immune osteogenesis by CS and cytokine osteogenesis by BMP-2. Thus, the present study revealed a practical avenue for the promotion of ligament-bone healing through the development of a triple-nano-coating engineered ligament combining immunoregulatory anti-fibrogenesis and sequential-synergistic osteogenesis, which holds a great potential for improving the clinical efficacy of ligament graft in ACL reconstruction. STATEMENT OF SIGNIFICANCE: A triple-nano-coating polyethylene terephthalate (PET) graft was developed by polydopamine self-assembly, chondroitin sulfate (CS) chemical-grafting and BMP-2 physical-immobilization to facilitate robust ligament-bone healing. This study demonstrated that the multifunctional ligament grafts could reshape the local immune microenvironment by regulating macrophage phenotype and immune cytokine secretion to inhibit the fibrous hyperplasia and regulate stem cell towards osteogenic differentiation to promote bone regeneration. The present study demonstrates that efficient ligament-bone healing is achieved via the combination of immunoregulatory anti-fibrogenesis and dual osteogenesis of immunoregulation and cytokine induction.


Assuntos
Reconstrução do Ligamento Cruzado Anterior , Osteogênese , Osso e Ossos , Ligamentos , Polietilenotereftalatos
13.
Photobiomodul Photomed Laser Surg ; 38(11): 694-702, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33103954

RESUMO

Objective: We developed an implantable wireless blue micro light-emitting diode (micro-LED) device and evaluated the utility of continuous antimicrobial blue light (aBL) irradiation emitted from this micro-LED for root canal disinfection. Methods: An implantable wireless blue micro-LED device (peak wavelength: 410 nm, maximum power: 15 mW) was developed to be placed in the root canal. Optical transmission of the device in human dentin tissue was simulated using Monte Carlo ray-tracing method. The bactericidal effect of low-level aBL on planktonic root canal infection-related bacteria [Enterococcus faecalis, methicillin-resistant Streptococcus aureus (MRSA), and Prevotella intermedia] was evaluated by colony counting. The biocompatibility of continuous low-level aBL exposure was evaluated by infrared thermal imaging and cell viability tests. Thirty extracted intact human single-rooted teeth were prepared and the root canals were infected with E. faecalis for 14 days to form biofilm. The infected root canals were randomly divided into three groups (n = 10), and treated with normal saline (group NS), calcium hydroxide (group CH), and micro-LED device (group aBL) for 3 and 7 days. The bactericidal effect of each group was evaluated by confocal laser scanning microscopy (CLSM) and scanning electron microscopy (SEM). Results: Monte Carlo simulation showed that blue light irradiation of the micro-LED device decreased exponentially with the light transmission distance through human dentin tissue. Planktonic E. faecalis, MRSA, and P. intermedia were significantly eliminated after irradiation with 432, 36, and 1.35 J/cm2 aBL, respectively (p < 0.05). Infrared thermal imaging and cell viability tests showed that continuous aBL exposure is biocompatible in vitro. CLSM and SEM analyses revealed that the micro-LED device had a greater antimicrobial effect than CH on E. faecalis biofilm in the root canal. Conclusions: The wireless blue micro-LED device is a promising and user-friendly approach for root canal disinfection that will facilitate infection control in the root canal using aBL.


Assuntos
Anti-Infecciosos , Fotoquimioterapia , Biofilmes , Cavidade Pulpar , Enterococcus faecalis , Humanos
14.
J Mater Chem B ; 7(48): 7756-7770, 2019 12 11.
Artigo em Inglês | MEDLINE | ID: mdl-31750849

RESUMO

Optimal integration between the polyethylene terephthalate (PET) graft and host bone is a prerequisite to obtain a satisfactory outcome after graft implantation for ligament reconstruction. Recent studies indicate that complex biosignals including immunoregulation, cell recruitment, and osteogenic differentiation provided by the extracellular matrix (ECM) are conducive to promoting osseointegration. In the present study, a chondroitin sulfate (CS)/polydopamine-modified PET graft was developed to regulate the local immune microenvironment, guide stem cell behavior, and promote new bone formation. We found that CS-modified PET grafts significantly regulated the macrophage phenotype switching from M1 to M2 and promoted the expression of pro-repair cytokines including interleukin (IL)-4, IL-10 and transforming growth factor (TGF)-ß1. Moreover, the immunoregulatory function of CS-modified PET guided stem cell behaviors, including recruitment, adhesion, and proliferation, and enhanced the osteogenic differentiation of stem cells. In vivo experiments confirmed that CS-modified PET switched the local immune microenvironment status from pro-inflammatory to anti-inflammatory, up-regulated osteogenic marker expression, and promoted the bone regeneration process, so as to achieve graft-bone osseointegration. These results indicate that an ECM-biomimetic immunoregulatory coating is an effective approach to promote graft integration. This study proposes an effective strategy for an artificial graft to achieve graft-bone osseointegration through immunoregulatory osteogenesis.


Assuntos
Biomimética/métodos , Matriz Extracelular/imunologia , Osseointegração , Polietilenotereftalatos/química , Animais , Regeneração Óssea/efeitos dos fármacos , Sulfatos de Condroitina/química , Humanos , Indóis/química , Osseointegração/efeitos dos fármacos , Osteogênese , Polímeros/química , Próteses e Implantes
15.
Biomed Res Int ; 2016: 5878645, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27379249

RESUMO

We explored a novel poly(3-hydroxybutyrate) (PHB) nanoparticle loaded with hydrophilic recombinant human BMP-2 with amphiphilic phospholipid (BPC-PHB NP) for a rapid-acting and long-acting delivery system of BMP-2 for osteogenic differentiation. The BPC-PHB NPs were prepared by a solvent evaporation method and showed a spherical particle with a mean particle size of 253.4 nm, mean zeta potential of -22.42 mV, and high entrapment efficiency of 77.18%, respectively. For BPC-PHB NPs, a short initial burst release of BMP-2 from NPs in 24 h was found and it has steadily risen to reach about 80% in 20 days for in vitro test. BPC-PHB NPs significantly reduced the burst release of BMP-2, as compared to that of PHB NPs loading BMP-2 without PL (B-PHB NPs). BPC-PHB NPs maintained the content of BMP-2 for a long-term osteogenic differentiation. The OCT-1 cells with BPC-PHB NPs have high ALP activity in comparison with others. The gene markers for osteogenic differentiation were significantly upregulated for sample with BPC-PHB NPs, implying that BPC-PHB NPs can be used as a rapid-acting and long-acting BMP-2 delivery system for osteogenic differentiation.


Assuntos
Proteína Morfogenética Óssea 2/administração & dosagem , Diferenciação Celular/efeitos dos fármacos , Sistemas de Liberação de Medicamentos , Osteogênese/efeitos dos fármacos , Proteína Morfogenética Óssea 2/química , Linhagem Celular , Liberação Controlada de Fármacos , Humanos , Hidroxibutiratos/administração & dosagem , Hidroxibutiratos/química , Nanopartículas/administração & dosagem , Nanopartículas/química , Osteoblastos/efeitos dos fármacos , Osteoblastos/ultraestrutura , Fosfolipídeos/administração & dosagem , Fosfolipídeos/química , Poliésteres/administração & dosagem , Poliésteres/química , Proibitinas , Tensoativos/administração & dosagem , Tensoativos/química
16.
Adv Mater ; 26(39): 6734-41, 2014 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-25147084

RESUMO

Four-arm star-shaped copolymers, TPE-star-P(DMA-co-BMA-co-Gd), containing TPE cores with an aggregation-induced emission (AIE) feature, a T 1 -type magnetic resonance (MR) contrast agent, and amphiphilic cationic arms, are synthesized. By taking advantage of non-covalent interactions between star copolymers and bacteria surfaces, bimodal fluorometric/MR detection and concomitant inhibition of both Gram-positive and Gram-negative bacteria strains in aqueous media are explored.


Assuntos
Escherichia coli/efeitos dos fármacos , Escherichia coli/isolamento & purificação , Interações Hidrofóbicas e Hidrofílicas , Fenômenos Magnéticos , Polímeros/química , Polímeros/farmacologia , Antibacterianos/química , Antibacterianos/farmacologia , Permeabilidade da Membrana Celular/efeitos dos fármacos , Escherichia coli/citologia , Corantes Fluorescentes/química , Corantes Fluorescentes/farmacologia , Compostos Heterocíclicos com 1 Anel/química
17.
Biomaterials ; 35(5): 1618-26, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24239302

RESUMO

The development of portable and inexpensive detection methods can significantly contribute to the prevention of water-borne infectious diseases caused by pathogenic bacteria. Here we designed a nanosystem capable of both bacterial detection and inhibition, where polyion complex (PIC) micelles are constructed from negatively-charged tetraphenylethylene (TPE) sulfonate derivatives, which exhibit the aggregation-induced emission (AIE) feature, and cationic diblock copolymers, poly(ethylene oxide)-b-quaternized poly(2-(dimethylamino)ethyl methacrylate) (PEO-b-PQDMA). Upon contacting with bacteria, the PIC nanosystem disintegrates presumably due to competitive binding of polycation blocks with negatively-charged bacterial surfaces. This process is accompanied by a conspicuous quenching of TPE fluorescence emission, serving as a real-time module for microbial detection. Furthermore, the sharp decrease in CFU is indicative of prominent anti-microbial activities. Thus, PIC micelles possess dual functions of fluorometric detection and inhibition for bacteria in aqueous media. By tuning the charge density of TPE sulfonate derivatives and chain length of cationic PQDMA blocks, optimal performance against Gram-negative Escherichia coli has been achieved with a detection limit of 5.5 × 10(4) CFU/mL and minimum inhibitory concentration (MIC) of 19.7 µg/mL. Tests against Gram-positive Staphylococcus aureus were also conducted to demonstrate versatility of the nanosystem.


Assuntos
Antibacterianos/farmacologia , Bactérias/efeitos dos fármacos , Micelas , Nanopartículas , Espectrometria de Fluorescência/métodos , Meios de Cultura , Íons , Testes de Sensibilidade Microbiana , Microscopia Eletrônica de Varredura , Polímeros/química , Polímeros/farmacologia , Água
18.
Int J Biol Macromol ; 62: 663-9, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24099939

RESUMO

Soda lignin was first thermostabilized prior to carbonization. The composition, structures and thermal properties of treated lignin were investigated by EA, TGA-MS, (13)C NMR, TGA, and Raman. EA and TGA-MS results showed that the hydrogen content decreased continuously and the oxygen content increased up to 260 °C then decreased and the carbon content increased passively during thermostabilization. (13)C NMR results revealed that thermostabilization could be divided into three stages according to the evolution of the oxygenated structures content: <260 °C, 260-290 °C, >290 °C. Raman analysis showed that R values at each carbonization temperature were concave-down and non-symmetrical parabolic type and the 260 °C thermostabilized lignin after 1400 °C carbonized obtained the minimum R value 1.84. TGA results indicated that overall yields reflecting thermal stability of the thermostabilized samples, especially thermostabilized at 260-290 °C, were higher than that of untreated lignin.


Assuntos
Lignina/química , Termodinâmica , Grafite/química , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Análise Espectral Raman
19.
Anal Sci ; 28(5): 497-502, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22687930

RESUMO

An ultrasensitive voltammetric sensor, a simply coated graphene-Na?on suspension on a glass carbon electrode surface, was fabricated and used to investigate the electrochemical behavior of theophylline as described in the present paper. The results indicated that this voltammetric sensor exhibited a special recognition capacity to determine theophylline as well as having high sensitivity due to the excellent characteristics of graphene and the adsorption action of Nafion for theophylline. Under the selected condition using differential pulse voltammetry, the response peak currents had a linear relationship with the theophylline concentrations in two ranges from 1.0 × 10(-8) - 1.0 × 10(-6) and 2.0 × 10(-6) - 3.0 × 10(-5) mol L(-1) with a low detection limit of 6.0 × 10(-9) mol L(-1). Moreover, according to the results obtained in the analysis of theophylline in two standard samples, it demonstrated the applicability of present method into real sample determination.


Assuntos
Carbono/química , Técnicas Eletroquímicas , Polímeros de Fluorcarboneto/química , Vidro/química , Teofilina/análise , Eletroquímica , Eletrodos , Propriedades de Superfície
20.
Artigo em Inglês | MEDLINE | ID: mdl-22902584

RESUMO

One interesting pentanuclear zinc coordination polymer, [Zn(5)(OH)(2)(DTBA)(4)](n) (1) (DTBA=2,2'-dithiobisbenzoic acid) has been synthesized by hydrothermal method, and characterized by X-ray single crystal diffraction, elemental analyses, IR and TGA. The pentanuclear zinc unit exhibits pentagon configuration, which acts as secondary building unit to construct a one-dimensional chain structure by DTBA ligands. As far as we know, this kind of pentagon zinc unit is unprecedented. In addition, upon the excitation at 390 nm, the blue-fluorescence at 448 nm of the compound 1 was observed.


Assuntos
Complexos de Coordenação/química , Complexos de Coordenação/síntese química , Luminescência , Polímeros/química , Polímeros/síntese química , Zinco/química , Ácido Benzoico/química , Cristalografia por Raios X , Ligantes , Conformação Molecular , Espectrometria de Fluorescência , Espectrofotometria Infravermelho
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