RESUMO
Single-chain polymer nanoparticles (SCNPs) are soft matter constructed by intrachain crosslinks, with promising prospects in detection and catalysis. Herein, a fluorescent core (SCNPs) with aggregation-induced emission (AIE) is prepared, applying for H2 O2 detection through intermolecular heavy-atom effect. In detail, the SCNPs precursors are synthesized by ring-opening copolymerization. Then the SCNPs are prepared by intramolecularly cross-linking via olefin metathesis. Imitating the structure of AIE dots, SCNPs are encapsulated by H2 O2 -responsive polymers. Probably due to the stable secondary structure of SCNPs, the obtained micelles show stable fluorescence performance. Furthermore, as the heavy-atom, tellurium is introduced into the carriers to construct the heavy-atom effect. In this micelle-based system, the SCNPs act as the fluorescent core, and the stimuli-responsive polymer acts as the carrier and the fluorescent switch. The hydrophilicity of the tellurium-containing segment is affected by the concentration of H2 O2 , resulting in a change in the distance from the SCNPs, which ultimately leads to a change in the fluorescence intensity. Furthermore, tellurium is particularly sensitive to H2 O2 , which can detect low concentrations of H2 O2 . The SCNPs are merged with AIE materials, with the hope of exploring new probe designs.
Assuntos
Nanopartículas , Polímeros , Micelas , Nanopartículas/química , Polimerização , Polímeros/química , TelúrioRESUMO
Stimuli-responsive polymers that can undergo conformational changes with external triggers have enabled themselves as smart materials for various utilizations, among which biodegradability is of particular importance to be engineered for biomedical application. In this study, a thermo and pH dual responsive polypeptide (N, N-dimethylaminoethyl acrylate-modified poly(l-cysteine)) (PLC-g-DMAEA) was prepared by the combination of N-carboxyanhydride ring-open polymerization and thiol-ene click chemistry. The biodegradable poly(l-cysteine) (PLC) with pendant thiol groups provided an easily clickable backbone for postmodification, which was demonstrated by reacting with a well-known monomer of N, N-dimethylaminoethyl acrylate (DMAEA) to achieve both temperature and pH responsiveness. The irreversible thermo-response of PLC-g-DMAEA could be attributed to the ordered ß-sheets formed upon heating, leading to the trapped side groups with poor water accessibility. Moreover, this copolymer precipitated at pH ranging from 7.5 to 9.7, but protonation of tertiary amine groups (pH < 7.5) and salt forming of masked thiol groups (pH > 9.7) rendered it soluble in water. Our results revealed that a ready available vinyl monomer could be easily clicked onto the biodegradable PLC and its stimuli responsiveness would be reserved. Moreover, the primary and secondary structures of PLC might influence the conformation, thus leading to the unique responsive behavior of the resulted copolymer.
Assuntos
Acrilatos/química , Metilaminas/química , Peptídeos/síntese química , Química Click , Concentração de Íons de Hidrogênio , Espectroscopia de Ressonância Magnética , Peptídeos/química , Transição de Fase , Polimerização , Espectroscopia de Infravermelho com Transformada de Fourier , Análise Espectral Raman , Compostos de Sulfidrila/química , TemperaturaRESUMO
Herein, a new class of main chain functionalized aliphatic polycarbonates with sulfur/selenium functional groups on the backbone is reported. Sulfur/selenium-containing cyclic carbonate monomers (MR ) are designed and synthesized by enzyme-catalyzed intermolecular macro-ring closure of related diols. The proposed synthetic strategy is tolerant of other functionalities such as N-substituted groups. The ring opening polymerization (ROP) of MR occurs readily as a versatile route to generate a new family of main chain sulfur/selenium substituted aliphatic polycarbonates (PR) with predictable molecular weights (MW), narrow molecular-weight distribution and controlled copolymer composition. The resultant polymers can be oxidized and/or reduced by treatment with hydrogen peroxide (H2 O2 ) or dithiothreitol (DTT), highlighting their potential for applications in the stimuli-responsive field and inflammation/cancer targeting. With these desirable results, it is revealed that this versatile technique can provide a broad-reaching method to the next generation of innovative materials, especially, well-defined biodegradable chalcogen-based main chain functional biomaterials.
RESUMO
With increasing troubles in bacterial contamination and antibiotic-resistance, new materials possessing both biocompatibility and antimicrobial efficacy are supposed to be developed for future biomedical application. Herein, we demonstrated a chemo-enzymatic ring opening polymerization (ROP) approach for block copolyester, that is, poly(4-benzyl formate piperidine lactone- b-ω-pentadecalactone) (PNPIL- b-PPDL), in a one-pot two-step process. Afterward, cationic poly(4-piperidine lactone- b-ω-pentadecalactone) (PPIL- b-PPDL) with pendent secondary amino groups was obtained via acidic hydrolysis of PNPIL- b-PPDL. The resulting cationic block copolyester exhibited high antibacterial activity against Gram negative E. coli and Gram positive S. aureus, while showed low toxicity toward NIH-3T3 cells. Moreover, the antibacterial property, cytotoxicity and degradation behavior could be tuned simply by variation of PPIL content. Therefore, we anticipate that such cationic block copolymers could potentially be applied as biomaterials for medicine or implants.
Assuntos
Antibacterianos/síntese química , Lactonas/química , Piperidinas/química , Células 3T3 , Animais , Antibacterianos/toxicidade , Camundongos , Staphylococcus aureus/efeitos dos fármacosRESUMO
Copolypept(o)ides of polysarcosine (PSar) and poly(N-isopropyl-L-glutamine) (PIGA) with random and block sequence structures were synthesized by ring-opening polymerization (ROP) of sarcosine N-carboxyanhydrides (Sar-NCA) and γ-benzyl-l-glutamate N-carboxyanhydrides (BLG-NCA) and post modification. With different distribution of Sar along the main chain, H-bonding pattern and secondary structure of polypeptides were turned, as well as aggregation and gelation behavior. Both copolypept(o)ides formed hydrogels above their critical gelation concentrations (CGCs) without thermo-sensitivity, which was normally reserved for PEG copolypeptides (eg, PEG-b-PIGA). In particular, a different mechanism from previously reported micellar percolation or fibrillar entanglement was suggested for gelation of the random copolypept(o)ide. Therefore, hydrogels from copolymers of PSar and PIGA represented a new approach to construct easy-handling, biocompatible, biodegradable and thermo-stable gels that could potentially be applied in biomedical fields.
Assuntos
Anidridos/química , Biopolímeros/química , Glutamatos/química , Peptídeos/química , Polimerização , Anidridos/síntese química , Glutamatos/síntese química , Hidrogéis/química , Indóis/síntese química , Indóis/química , Peptídeos/síntese química , Estrutura Secundária de Proteína , Sarcosina/análogos & derivados , Sarcosina/síntese química , Sarcosina/químicaRESUMO
This study focuses on the synthesis of Pluronic-b-poly(ε-caprolactone) bearing benzyl-oxycarbonylmethyl and carboxylic groups and the comparative study to investigate the influence of the different pendant groups on the cellular behavior. The functionalized Pluronic-b-poly(ε-caprolactone) bearing two kinds of pendant groups are synthesized via ring-opening polymerization of ε-caprolactone and 6-(benzyl-oxycarbonyl methyl)-ε-caprolactone and followed by deprotection respectively. The structure of the copolymers is confirmed and the polymeric micelles are formed by an emulsion/solvent evaporation technique. The critical micelle concentrations are improved compared with Pluronic F127, the morphologies of the micelles are spherical with the diameter on nano scale and good colloidal stability. The copolymers have good cytocompatibility and the comparative study reveals that cellular internalization, digesting by lysosome and intracellular distribution are affected by the pendant groups, moreover, the endocytosis pathway is determined by the pendant groups. Therefore, the definite internalization mechanism is beneficial for the design of polymeric micellar carriers to achieve intra- or extracellular modes of drug delivery and provide better access to either cell membrane or intracellular organelles.
Assuntos
Cumarínicos/química , Portadores de Fármacos/química , Glioma/química , Polietilenos/química , Polipropilenos/química , Frações Subcelulares/química , Tiazóis/química , Animais , Linhagem Celular , Difusão , Teste de Materiais , Micelas , Tamanho da Partícula , RatosRESUMO
In tissue engineering, incorporation of bone morphogenetic protein-2 (BMP-2) into biomaterial scaffolds is an attractive strategy to stimulate bone repair. However, suboptimal release of BMP-2 remains a great concern, which may cause unfavorable bone formation as well as severe inflammation. In this study, genipin-cross-linked gelatin entrapped with recombinant human BMP-2 (rhBMP-2) was exploited to decorate the interior surface of three-dimensional porous poly(ε-caprolactone) (PCL) scaffolds. With gelatin-coating, PCL scaffolds demonstrated enhanced water uptake and improved compressive moduli. Intriguingly, a unique release profile of rhBMP-2 composed of a transient burst release followed by a sustained release was achieved in coated scaffolds. These coated scaffolds well supported growth and osteogenesis of human mesenchymal stem cells (hMSCs) in vitro, indicating the retaining of rhBMP-2 bioactivity. When hMSCs-seeded scaffolds were implanted subcutaneously in nude mice for 4 weeks, better bone formation was observed in gelatin/rhBMP-2-coated scaffolds. Specifically, the spatial distribution of newly formed bone was more uniform in gelatin-coated scaffolds than in uncoated scaffolds, which displayed preferential bone formation at the periphery. These results collectively demonstrated that gelatin-coating of porous PCL scaffolds is a promising approach for delivering rhBMP-2 to stimulate improved bone regeneration.
Assuntos
Proteína Morfogenética Óssea 2/química , Gelatina/química , Células-Tronco Mesenquimais/fisiologia , Osteogênese/fisiologia , Poliésteres/química , Alicerces Teciduais/química , Fator de Crescimento Transformador beta/química , Animais , Proteína Morfogenética Óssea 2/administração & dosagem , Bovinos , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/química , Feminino , Gelatina/administração & dosagem , Humanos , Células-Tronco Mesenquimais/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Osteogênese/efeitos dos fármacos , Poliésteres/administração & dosagem , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/química , Fator de Crescimento Transformador beta/administração & dosagemRESUMO
Antibacterial hydrogel has emerged as an excellent candidate for wound dressing with the ability to eliminate infection and promote wound healing. Herein, a dynamic hydrogel is developed by Schiff base reaction of mixed charged polypeptides and oxidized dextran (ODex). Specifically, biodegradable polypeptides of 1-(propylthio)acetic acid-3-butylimidazole-modified poly(L-lysine) (PLL-PBIM) and adipate dihydrazide-modified poly(L-glutamic acid) (PLG-ADH) are achieved with tunable substitution and charge. By mixing with ODex, charged polypeptides of PLL-PBIM and PLG-ADH led to an injectable and self-healing hydrogel in seconds. The injectable and self-healing performances of the hydrogels are ascribed to the reversible imine and hydrazone bonds formed between polypeptides and ODex. The positively charged hydrogels exhibited over 95% antibacterial activity against E. coli and S. aureus. An optimized balancing of PLG-ADH and PLL-PBIM significantly reduced the hemolysis rate and cytotoxicity of hydrogels. Therefore, the dynamic hydrogel with excellent biocompatibility and inherently antibacterial ability can have potential application for wound dressing.
Assuntos
Adesivos , Hidrogéis , Hidrogéis/farmacologia , Hidrogéis/química , Staphylococcus aureus , Escherichia coli , Antibacterianos/farmacologia , Antibacterianos/química , Bandagens , PeptídeosRESUMO
Glutathione (GSH) depletion-induced ferroptosis has emerged as a promising treatment for malignant cancer. It works by inactivating glutathione peroxidase 4 (GPX4) and facilitating lipid peroxidation. However, effectively delivering inducers and depleting intracellular GSH remains challenging due to the short half-lives and high hydrophobicity of small-molecule ferroptosis inducers. These inducers often require additional carriers. Herein, diselenide-containing polymers can consume GSH to induce ferroptosis for pancreatic cancer therapy. The diselenide bonds are controllably built into the backbone of the polycarbonate with a targeting peptide CRGD (Cys-Arg-Gly-Asp), which allows for self-assembly into stable nanoparticles (denoted CRNSe) for self-delivery. Significantly, at a concentration of 12 µg mL-1, CRNSe binds to the active site cysteine of GSH resulting in a thorough depletion of GSH. In contrast, the disulfide-containing analog only causes a slight decrease in GSH level. Moreover, the depletion of GSH inactivates GPX4, ultimately inducing ferroptosis due to the accumulation of lipid peroxide in BxPC-3 cells. Both in vitro and in vivo studies have demonstrated that CRNSe exhibits potent tumor suppressive ability with few side effects on normal tissue. This study validates the anti-tumor mechanism of diselenide-containing polymers in addition to apoptosis and also provides a new strategy for inherently inducing ferroptosis in cancer therapy.
Assuntos
Ferroptose , Glutationa , Ferroptose/efeitos dos fármacos , Humanos , Glutationa/metabolismo , Animais , Linhagem Celular Tumoral , Camundongos , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Nanopartículas/química , Antineoplásicos/farmacologia , Antineoplásicos/química , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Polímeros/química , Polímeros/farmacologia , Camundongos Nus , Cimento de Policarboxilato/química , Oligopeptídeos/química , Oligopeptídeos/farmacologia , Camundongos Endogâmicos BALB CRESUMO
Alginate-based materials present promising potential for emergency hemostasis due to their excellent properties, such as procoagulant capability, biocompatibility, low immunogenicity, and cost-effectiveness. However, the inherent deficiencies in water solubility and mechanical strength pose a threat to hemostatic efficiency. Here, we innovatively developed a macromolecular cross-linked alginate aerogel based on norbornene- and thiol-functionalized alginates through a combined thiol-ene cross-linking/freeze-drying process. The resulting aerogel features an interconnected macroporous structure with remarkable water-uptake capacity (approximately 9000 % in weight ratio), contributing to efficient blood absorption, while the enhanced mechanical strength of the aerogel ensures stability and durability during the hemostatic process. Comprehensive hemostasis-relevant assays demonstrated that the aerogel possessed outstanding coagulation capability, which is attributed to the synergistic impacts on concentrating effect, platelet enrichment, and intrinsic coagulation pathway. Upon application to in vivo uncontrolled hemorrhage models of tail amputation and hepatic injury, the aerogel demonstrated significantly superior performance compared to commercial alginate hemostatic agent, yielding reductions in clotting time and blood loss of up to 80 % and 85 %, respectively. Collectively, our work illustrated that the alginate porous aerogel overcomes the deficiencies of alginate materials while exhibiting exceptional performance in hemorrhage, rendering it an appealing candidate for rapid hemostasis.
Assuntos
Alginatos , Géis , Hemostasia , Hemostáticos , Alginatos/química , Animais , Hemostáticos/química , Hemostáticos/farmacologia , Hemostasia/efeitos dos fármacos , Géis/química , Porosidade , Hemorragia/tratamento farmacológico , Coagulação Sanguínea/efeitos dos fármacos , Camundongos , Masculino , Reagentes de Ligações Cruzadas/química , Materiais Biocompatíveis/química , Materiais Biocompatíveis/farmacologiaRESUMO
Phenotypic plasticity is a rising cancer hallmark, and lung adeno-to-squamous transition (AST) triggered by LKB1 inactivation is significantly associated with drug resistance. Mechanistic insights into AST are urgently needed to identify therapeutic vulnerability in LKB1-deficient lung cancer. Here, we find that ten-eleven translocation (TET)-mediated DNA demethylation is elevated during AST in KrasLSL-G12D/+; Lkb1L/L (KL) mice, and knockout of individual Tet genes reveals that Tet2 is required for squamous transition. TET2 promotes neutrophil infiltration through STAT3-mediated CXCL5 expression. Targeting the STAT3-CXCL5 nexus effectively inhibits squamous transition through reducing neutrophil infiltration. Interestingly, tumor-infiltrating neutrophils are laden with triglycerides and can transfer the lipid to tumor cells to promote cell proliferation and squamous transition. Pharmacological inhibition of macropinocytosis dramatically inhibits neutrophil-to-cancer cell lipid transfer and blocks squamous transition. These data uncover an epigenetic mechanism orchestrating phenotypic plasticity through regulating immune microenvironment and metabolic communication, and identify therapeutic strategies to inhibit AST.
Assuntos
Quimiocina CXCL5 , Proteínas de Ligação a DNA , Dioxigenases , Neoplasias Pulmonares , Neutrófilos , Proteínas Proto-Oncogênicas , Fator de Transcrição STAT3 , Animais , Neutrófilos/metabolismo , Fator de Transcrição STAT3/metabolismo , Camundongos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/genética , Proteínas de Ligação a DNA/metabolismo , Proteínas de Ligação a DNA/genética , Quimiocina CXCL5/metabolismo , Quimiocina CXCL5/genética , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas/genética , Humanos , Dioxigenases/metabolismo , Pinocitose , Linhagem Celular Tumoral , Infiltração de Neutrófilos , Camundongos Knockout , Camundongos Endogâmicos C57BL , Metabolismo dos LipídeosRESUMO
Elastomeric scaffolds, individually customized to mimic the structural and mechanical properties of natural tissues have been used for tissue regeneration. In this regard, polyester elastic scaffolds with tunable mechanical properties and exceptional biological properties have been reported to provide mechanical support and structural integrity for tissue repair. Herein, poly(4-methyl-ε-caprolactone) (PMCL) was first double-terminated by alkynylation (PMCL-DY) as a liquid precursor at room temperature. Subsequently, three-dimensional porous scaffolds with custom shapes were fabricated from PMCL-DY via thiol-yne photocrosslinking using a practical salt template method. By manipulating the Mn of the precursor, the modulus of compression of the scaffold was easily adjusted. As evidenced by the complete recovery from 90% compression, the rapid recovery rate of >500 mm min-1, the extremely low energy loss coefficient of <0.1, and the superior fatigue resistance, the PMCL20-DY porous scaffold was confirmed to harbor excellent elastic properties. In addition, the high resilience of the scaffold was confirmed to endow it with a minimally invasive application potential. In vitro testing revealed that the 3D porous scaffold was biocompatible with rat bone marrow stromal cells (BMSCs), inducing BMSCs to differentiate into chondrogenic cells. In addition, the elastic porous scaffold demonstrated good regenerative efficiency in a 12-week rabbit cartilage defect model. Thus, the novel polyester scaffold with adaptable mechanical properties may have extensive applications in soft tissue regeneration.
RESUMO
Diagnostic and therapeutic illumination on internal organs and tissues with high controllability and adaptability in terms of spectrum, area, depth, and intensity remains a major challenge. Here, we present a flexible, biodegradable photonic device called iCarP with a micrometer scale air gap between a refractive polyester patch and the embedded removable tapered optical fiber. ICarP combines the advantages of light diffraction by the tapered optical fiber, dual refractions in the air gap, and reflection inside the patch to obtain a bulb-like illumination, guiding light towards target tissue. We show that iCarP achieves large area, high intensity, wide spectrum, continuous or pulsatile, deeply penetrating illumination without puncturing the target tissues and demonstrate that it supports phototherapies with different photosensitizers. We find that the photonic device is compatible with thoracoscopy-based minimally invasive implantation onto beating hearts. These initial results show that iCarP could be a safe, precise and widely applicable device suitable for internal organs and tissue illumination and associated diagnosis and therapy.
Assuntos
Óptica e Fotônica , Fototerapia , Fibras Ópticas , Fármacos Fotossensibilizantes , Desenho de EquipamentoRESUMO
Epigallocatechin-3-O-gallate (EGCG) is a green biomedical agent for promoting wound healing, which possess excellent antibacterial, antioxidant and anti-inflammatory activities. For improving the low bioavailability challenges of EGCG in vivo, we had successful created a low-cost and simple wound dressing Poly (L-Lactic-co-caprolactone) (PLCL)/Gelatin/EGCG/Core-shell nanofiber membrane (PGEC) with drug sustained release capacity through coaxial electrospinning technology. In vitro experimental indicated that the core-shell structure wound dressing had excellent biocompatibility, antibacterial and antioxidant ability, which could support cell viability and proliferation, encourage re-epithelialization during the healing process, inhibit subsequent wound infection and thus promote wound regeneration. In vivo experimental demonstrated that PGEC wound dressing could promote wound healing, the histological results further demonstrated that PGEC not only facilitated early wound closure but also influenced cellular differentiation and tissue organization. Meanwhile, PGEC had excellent hemostatic ability. Taken all together, we believed that the PGEC wound dressing, which could localize delivery of EGCG, had high potential clinical application for promoting wound healing, hemostasis or other related clinical applications in the future.
Assuntos
Antibacterianos/farmacologia , Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Gelatina/química , Membranas Artificiais , Nanofibras/química , Cicatrização , Animais , Antibacterianos/química , Anti-Inflamatórios/química , Antioxidantes/química , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Fenômenos Químicos , Camundongos , Testes de Sensibilidade Microbiana , Nanofibras/ultraestruturaRESUMO
Despite the fact that heart transplantation (HTx) is a relatively mature procedure, heart ischemic and reperfusion (I/R) injury during HTx remains a challenge. Even after a successful operation, the heart will be at risk of primary graft failure and mortality during the first year. In this study, temperature-sensitive polymer poly(N-n-propylacrylamide-co-N-tert-butyl acrylamide) (PNNTBA) was coated on diallyl trisulfide (DATS)-loaded mesoporous silica nanoparticles (DATS-MSN) to synthesize hypothermia-triggered hydrogen sulfide (H2S) releasing particles (HT-MSN). Because the PNNTBA shell dissolves in phosphate-buffered saline at 4 °C, the loaded DATS could continuously release H2S within 6 h when activated by glutathione (GSH). Furthermore, after co-culturing biocompatible HT-MSN with cardiomyocytes, H2S released from HT-MSN at 4 °C was found to protect cardiomyocytes from ischemic and reperfusion (I/R) injury. In detail, the rate of cell apoptosis and lactate dehydrogenase activity was decreased, as manifested by increased BCL-2 expression and decreased BAX expression. More importantly, in an isolated heart preservation experiment, HT-MSN demonstrated potent protection against cardiac I/R injury and reduced expression of inflammatory factors TNF-α and IL-1ß. This study provided a new method for the controlled release of H2S by the donor and myocardial protection from I/R injury.
Assuntos
Sulfeto de Hidrogênio , Hipotermia , Preparações de Ação Retardada/metabolismo , Preparações de Ação Retardada/farmacologia , Humanos , Sulfeto de Hidrogênio/metabolismo , Sulfeto de Hidrogênio/farmacologia , Hipotermia/metabolismo , Miocárdio/metabolismo , Dióxido de Silício/metabolismo , Dióxido de Silício/farmacologiaRESUMO
This study aimed to optimize poly(ethylene glycol)-b-poly(ε-caprolactone) (PEG-b-PCL)-based amphiphilic block copolymers for achieving a better micellar drug delivery system (DDS) with improved solubilization and delivery of doxorubicin (DOX). First, the Flory-Huggins interaction parameters between DOX and the core-forming segments [i.e., poly(ε-caprolactone) (PCL) and poly[(ε-caprolactone-co-γ-(carbamic acid benzyl ester)-ε-caprolactone] (P(CL-co-CABCL))] was calculated to assess the drug-polymer compatibility. The results indicated a better compatibility between DOX and P(CL-co-CABCL) than that between DOX and PCL, motivating the synthesis of monomethoxy-poly(ethylene glycol)-b-poly[(ε-caprolactone-co-γ-(carbamic acid benzyl ester)-ε-caprolactone] (mPEG-b-P(CL-co-CABCL)) block copolymer. Second, two novel block copolymers of mPEG-b-P(CL-co-CABCL) with different compositions were prepared via ring-opening polymerization of CL and CABCL using mPEG as a macroinitiator and characterized by (1)H NMR, FT-IR, GPC, WAXD, and DSC techniques. It was found that the introduction of CABCL decreased the crystallinity of mPEG-b-PCL copolymer. Micellar formation of the copolymers in aqueous solution was investigated with fluorescence spectroscopy, DLS and TEM. mPEG-b-P(CL-co-CABCL) copolymers had a lower critical micelle concentration (CMC) than mPEG-b-PCL and subsequently led to an improved stability of prepared micelles. Furthermore, both higher loading capacity and slower in vitro release of DOX were observed for micelles of copolymers with increased content of CABCL, attributed to both improved drug-core compatibility and favorable amorphous core structure. Meanwhile, DOX-loaded micelles facilitated better uptake of DOX by HepG2 cells and were mainly retained in the cytosol, whereas free DOX accumulated more in the nuclei. However, possibly because of the slower intracellular release of DOX, DOX-loaded micelles were less potent in inhibiting cell proliferation than free DOX in vitro. Taken together, the introduction of CABCL in the core-forming block of mPEG-b-PCL resulted in micelles with superior properties, which hold great promise for drug delivery applications.
Assuntos
Doxorrubicina/química , Sistemas de Liberação de Medicamentos , Lactonas/química , Polietilenoglicóis/química , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Doxorrubicina/farmacologia , Humanos , Lactonas/farmacologia , Micelas , Estrutura Molecular , Tamanho da Partícula , Polietilenoglicóis/farmacologia , Solubilidade , Relação Estrutura-Atividade , Propriedades de Superfície , Distribuição Tecidual , Células Tumorais CultivadasRESUMO
Antibacterial materials are highly demanded in treatment of bacterial infection, especially severe ones with multidrug-resistance. Herein, pH-responsive polypeptide, i.e., poly-L-lysine modified by 1-(propylthio)acetic acid-3-octylimidazolium and citraconic anhydride (PLL-POIM-CA), is synthesized by post-polymerization modification of poly-L-lysine (PLL) with 1-(propylthio)acetic acid-3-octylimidazolium (POIM) and citraconic anhydride (CA). It is observed that PLL-POIM-CA is stable under normal physiological condition, while CA cleaves rapidly at weakly acidic environment like bacterial infectious sites. The hydrolyzed PLL-POIM-CA exhibits excellent broad-spectrum antibacterial activities against Gram-negative bacteria of Escherichia coli and Gram-positive bacteria of Staphylococcus aureus and methicillin-resistant Staphylococcus aureus (MRSA). In particular, the minimum inhibitory concentration (MIC) against multidrug-resistant bacteria like MRSA is as low as 7.8 µg mL-1 . Moreover, PLL-POIM-CA exhibits good biocompatibility with mouse fibroblast cells (L929) in vitro and improved hemocompatibility with an HC50 exceeding 5000 µg mL-1 . Therefore, PLL-POIM-CA displays an excellent bacteria versus cells selectivity (HC50 /MIC) over 534, which is 53 times higher than natural antimicrobial peptide of indolicidin. It is further demonstrated in vivo that the antimicrobial polypeptide effectively accelerates MRSA-infected wound healing by relieving local inflammatory response. Therefore, this targeted antimicrobial polypeptide has broad application prospects for the treatment of multidrug-resistant bacterial infection.
Assuntos
Staphylococcus aureus Resistente à Meticilina , Infecções Estafilocócicas , Animais , Antibacterianos/farmacologia , Farmacorresistência Bacteriana Múltipla , Camundongos , Testes de Sensibilidade Microbiana , Proteínas Citotóxicas Formadoras de Poros/farmacologiaRESUMO
Combining rapid microbial discrimination with antibacterial properties, multi-functional biomacromolecules allow the timely diagnosis and effective treatment of infectious diseases. Through a two-step approach involving organocatalytic ring-opening copolymerization and thiol-ene modification, aggregation-induced emission (AIE) polycarbonates decorated with tertiary amines were prepared. After being ionized using acetic acid, the obtained cationic AIE polycarbonate with excellent water solubility showed bacteria imaging capabilities and antibacterial activities toward both Gram-positive S. aureus and Gram-negative E. coli. It was indicated via scanning electron microscope images that the bactericidal mechanism involved membrane lysis, consistent with most cationic polymers. Through further co-grafting carboxyl and tertiary amine groups, mixed-charge AIE polycarbonates were obtained. The isoelectric points of such mixed-charge AIE polycarbonates could be simply tuned based on the grafting ratio of positive and negative moieties. Compared with the cationic AIE polycarbonate, mixed-charge AIE polycarbonates allowed the rapid and selective imaging of S. aureus, but not E. coli. The selectivity probably arose from the lower binding forces between the mixed-charge AIE polycarbonates and the low-negative-charge components of the E. coli surface. Therefore, these biodegradable polycarbonates, which integrated selective bacteria imaging and antibiotic abilities, potentially suggest a precision medicine approach for infectious diseases. The overall synthesis approach and mixed-charge AIE polycarbonates provide new references for the design and application of bio-related AIE polymers.
Assuntos
Escherichia coli , Staphylococcus aureus , Antibacterianos , Cimento de Policarboxilato , PolímerosRESUMO
The application of nanotechnology-based drug delivery systems has resulted in great progresses in cancer therapy. However, current systems ultimately depend on the action of the drug itself and almost all nanocarriers only serve as excipients without any therapeutic efficacy. Herein, a drug-free therapeutic system is put forward, in which synthetic polymers themselves naturally exhibit effective anticancer activity without the loading of additional chemotherapy drugs. Aiming at this goal, amphiphilic poly(diselenide-carbonate) copolymers (PSeSeTMC), consisting of monomethyl ether poly(ethylene glycol) and diselenide-based polycarbonates, are designed and synthesized to build spherical nanoparticles, which show effective and broad-spectrum anticancer activities against multiple cancer cell lines and high selectivity toward cancer cells. Moreover, the anticancer activities can be well controlled by tuning the selenium contents in polymers. Mechanistic investigations indicate that PSeSeTMC can selectively induce cancer cells to express excessive reactive oxygen species, thereby leading to significant cellular apoptosis. In vivo antitumor studies further demonstrate high therapeutic efficacy and low side effects on normal tissue. Overall, this work provides a novel approach for cancer therapy by utilizing carriers themselves. Considering the fabrication process is pretty simple, this diselenide-based polymeric system has great potential in clinical translation.
Assuntos
Antineoplásicos , Nanopartículas , Neoplasias , Antineoplásicos/farmacologia , Apoptose , Linhagem Celular Tumoral , Portadores de Fármacos , Sistemas de Liberação de Medicamentos , Micelas , Neoplasias/tratamento farmacológico , Polietilenoglicóis , PolímerosRESUMO
Rapid hemostasis and antibacterial properties are essential for novel wound dressings to promote wound healing. In particular, timely and rapid hemostasis could be of benefit to reduce the mortality caused by excessive bleeding loss. Herein, we present a novel strategy of combining electrospinning technology with post-modification technology to prepare a multifunctional wound dressing, cellulose diacetate-based composite wound dressing (CDCE), with rapid hemostasis and antibacterial activity. It is interesting that the CDCE wound dressing had superhydrophilicity, high water absorption, and strong absorbing capacity, which could eliminate the exudate around the wound in a timely manner and further promote rapid hemostasis. Additionally, its excellent antibacterial properties could inhibit severe infection in the wound and accelerate wound healing. Based on these advantages, the novel CDCE wound dressing could promote wound contraction and further accelerate wound healing compared with the common traditional wound dressing gauze. Taken together, the multifunctional CDCE wound dressing has high potential for clinical application in the future.