RESUMO
Glucagon-like peptide-1 (GLP-1) is of particular interest for treating type 2 diabetes mellitus (T2DM), as it induces insulin secretion in a glucose-dependent fashion and has the potential to facilitate weight control. However, native GLP-1 is a short incretin peptide that is susceptible to fast proteolytic inactivation and rapid clearance from the circulation. Various GLP-1 analogs and bioconjugation of GLP-1 analogs have been developed to counter these issues, but these modifications are frequently accompanied by the sacrifice of potency and the induction of immunogenicity. Here, we demonstrated that with the conjugation of a zwitterionic polymer, poly(carboxybetaine) (pCB), the pharmacokinetic properties of native GLP-1 were greatly enhanced without serious negative effects on its potency and secondary structure. The pCB conjugated GLP-1 further provided glycemic control for up to 6 days in a mouse study. These results illustrate that the conjugation of pCB could realize the potential of using native GLP-1 for prolonged glycemic control in treating T2DM.
Assuntos
Diabetes Mellitus Tipo 2/sangue , Peptídeo 1 Semelhante ao Glucagon/química , Controle Glicêmico/métodos , Hipoglicemiantes/uso terapêutico , Polímeros/química , Animais , Diabetes Mellitus Tipo 2/tratamento farmacológico , Modelos Animais de Doenças , Peptídeo 1 Semelhante ao Glucagon/farmacocinética , Peptídeo 1 Semelhante ao Glucagon/uso terapêutico , Meia-Vida , Hipoglicemiantes/farmacocinética , Camundongos , Estrutura Secundária de ProteínaRESUMO
We report the synthesis of a zwitterionic carboxybetaine disulfide cross-linker (CBX-SS) and biodegradable poly(carboxybetaine) (PCB) hydrogels and nanocages (NCs) made using this cross-linker. The structure of CBX-SS combines zwitterionic carboxybetaine to confer nonfouling properties and a disulfide linkage to facilitate degradation. The physical, mechanical, and fouling characteristics of PCB hydrogels cross-linked with CBX-SS were investigated. Then, the degradation characteristics of CBX-SS-cross-linked hydrogels were evaluated through their weight loss and release of an encapsulated protein in a reducing environment. Furthermore, CBX-SS was applied to prepare degradable PCB NCs. Results show that encapsulating the highly immunogenic enzyme uricase in degradable PCB NCs eliminates or prevents an in vivo immune response to both the protein and polymer.
RESUMO
Achieving high selectivity of Li+ and Mg2+ is of paramount importance for effective lithium extraction from brines, and nanofiltration (NF) membrane plays a critical role in this process. The key to achieving high selectivity lies in the on-demand design of NF membrane pores in accordance with the size difference between Li+ and Mg2+ ions, but this poses a huge challenge for traditional NF membranes and difficult to be realized. In this work, we report the fabrication of polyamide (PA) NF membranes with ultra-high Li+/Mg2+ selectivity by modifying the interfacial polymerization (IP) process between piperazine (PIP) and trimesoyl chloride (TMC) with an oil-soluble surfactant that forms a monolayer at oil/water interface, referred to as OSARIP. The OSARIP benefits to regulate the membrane pores so that all of them are smaller than Mg2+ ions. Under the solely size sieving effect, an exceptional Mg2+ rejection rate of over 99.9% is achieved. This results in an exceptionally high Li+/Mg2+ selectivity, which is one to two orders of magnitude higher than all the currently reported pressure-driven membranes, and even higher than the microporous framework materials, including COFs, MOFs, and POPs. The large enhancement of ion separation performance of NF membranes may innovate the current lithium extraction process and greatly improve the lithium extraction efficiency.
RESUMO
The high mechanical strength and long-term resistance to the fibrous capsule formation are two major challenges for implantable materials. Unfortunately, these two distinct properties do not come together and instead compromise each other. Here, we report a unique class of materials by integrating two weak zwitterionic hydrogels into an elastomer-like high-strength pure zwitterionic hydrogel via a "swelling" and "locking" mechanism. These zwitterionic-elastomeric-networked (ZEN) hydrogels are further shown to efficaciously resist the fibrous capsule formation upon implantation in mice for up to 1 year. Such materials with both high mechanical properties and long-term fibrous capsule resistance have never been achieved before. This work not only demonstrates a class of durable and fibrous capsule-resistant materials but also provides design principles for zwitterionic elastomeric hydrogels.
RESUMO
The development of three-dimensional conductive scaffolds is vital to support the adhesion, proliferation and myocardial differentiation of stem cells in cardiac tissue engineering. Herein, we describe a facile approach for preparing a poly(3,4-ethylenedioxythiophene)/alginate (PEDOT/Alg) porous scaffold with a wide range of desirable properties. In the PEDOT/Alg scaffold, chemically crosslinked alginate networks are formed using adipic acid hydrazide as the crosslinker, and PEDOT is synthesized in situ in the alginate matrix simultaneously. PEDOT exists in the alginate matrix as particles and its morphology can be modulated by adjusting the ratio of PEDOT/alginate. The results also show that the swelling properties, degradation behaviors, mechanical strength and conductivity of the PEDOT/Alg scaffold can be controlled via adjusting the PEDOT/alginate ratio. The introduction of PEDOT can overcome the brittle nature of the pure alginate scaffold. Moreover, the PEDOT/Alg scaffold exhibits excellent conductivity (as high as 6 × 10-2 S cm-1). The introduction of PEDOT improves the protein absorption capacity of the alginate scaffold. To explore its potential application in cardiac tissue engineering, brown adipose-derived stem cells (BADSCs) are seeded in the prepared PEDOT/Alg porous scaffold. The results suggest that the PEDOT/Alg porous scaffold can support the attachment and proliferation of BADSCs. Moreover, it is beneficial for the cardiomyogenic differentiation of BADSCs, especially under electrical stimulation. Overall, we conclude that the PEDOT/Alg porous scaffold may represent an ideal platform to modulate the biological behaviors of BADSCs.
Assuntos
Tecido Adiposo Marrom/citologia , Alginatos/química , Compostos Bicíclicos Heterocíclicos com Pontes/química , Polímeros/química , Células-Tronco/fisiologia , Alicerces Teciduais , Adsorção , Diferenciação Celular , Proliferação de Células , Condutividade Elétrica , Estimulação Elétrica , Microscopia Eletrônica de Varredura , Miocárdio , Porosidade , Proteínas/química , Células-Tronco/ultraestruturaRESUMO
Hydrogels based on supramolecular noncovalent interactions have attracted great research interest but are still limited by relatively low mechanical strength and performance deterioration at subzero temperatures because of the formation of ice crystallization. In this study, an antifreezing and mechanically strong gelatin supramolecular organohydrogel is prepared via a simple strategy of immersing a gelatin pre-hydrogel in the citrate (Cit) water/glycerol mixture solution. In the organohydrogel, a part of water molecules are replaced by glycerol, which inhibits the formation of ice crystallization even at extremely low temperature. In addition, the formation of noncovalent interactions such as the hydrophobic aggregation induced by the salting-out effect, ionic interactions between the -NH3+ of gelatin and Cit3- anions, and hydrogen bonding between gelatin chains and glycerol endows the organohydrogels with high mechanical strength and toughness. The supramolecular organohydrogel can maintain its mechanical flexibility even at -80 °C or be stored for a long time. Moreover, the nature of noncovalent interactions endows the organohydrogel with intriguing thermoplasticity, good healable ability, and excellent adhesive behavior at various substrate surfaces.
RESUMO
Brown adipose derived stem cells (BADSCs) have become a promising stem cell treatment candidate for myocardial infarction because of their efficiently spontaneous differentiation capacity towards cardiomyocytes. The lack of existing cell passage protocols motivates us to develop a neotype 3D cell expansion technique for BADSCs. In this study, "clickable" zwitterionic starch based hydrogels are developed using methacrylate modified sulfobetaine derived starch with dithiol-functionalized poly (ethylene glycol) as crosslinker via the "thiol-ene" Michael addition reaction. Moreover, CGRGDS peptide is immobilized into the hydrogel via a similar "clickable" approach. Their Young's moduli range from 22.28 to 74.81â¯kPa depending on the concentration of precursor solutions. Excellent anti-fouling property is also presented owing to the introduction of zwitterionic moieties. BADSCs are homogeneously encapsulated in the hydrogels and then routinely cultured for 10 days. Results suggest a capacious cell proliferation and the extent increases with either the decrease of mechanical strength or the introduction of CGRGDS. More excitingly, the cell "stemness" is well maintained during this period and the expanded cells released from the hydrogels well keep the efficiently spontaneous cardiomyogenic differentiation capacity. Therefore, it is suggested that zwitterionic starch based hydrogel is able for the expansion and "stemness " maintenance of BADSCs.
Assuntos
Tecido Adiposo Marrom/citologia , Materiais Biocompatíveis/farmacologia , Diferenciação Celular/efeitos dos fármacos , Hidrogel de Polietilenoglicol-Dimetacrilato/farmacologia , Amido/química , Células-Tronco/citologia , Engenharia Tecidual/métodos , Tecido Adiposo Marrom/efeitos dos fármacos , Animais , Materiais Biocompatíveis/química , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Hidrogel de Polietilenoglicol-Dimetacrilato/química , Teste de Materiais , Oligopeptídeos/química , Ratos , Ratos Sprague-Dawley , Células-Tronco/efeitos dos fármacosRESUMO
Prediction of the diffusion coefficient of solute, especially bioactive molecules, in hydrogel is significant in the biomedical field. Considering the randomness of solute movement in a hydrogel network, a physical diffusion RMP-1 model based on obstruction theory was established in this study. The physical properties of the solute and the polymer chain and their interactions were introduced into this model. Furthermore, models RMP-2 and RMP-3 were established to understand and predict the diffusion behaviors of proteins in hydrogel. In addition, zwitterionic poly(sulfobetaine methacrylate) (PSBMA) hydrogels with wide range and fine adjustable mesh sizes were prepared and used as efficient experimental platforms for model validation. The Flory characteristic ratios, Flory-Huggins parameter, mesh size, and polymer chain radii of PSBMA hydrogels were determined. The diffusion coefficients of the proteins (bovine serum albumin, immunoglobulin G, and lysozyme) in PSBMA hydrogels were studied by the fluorescence recovery after photobleaching technique. The measured diffusion coefficients were compared with the predictions of obstruction models, and it was found that our model presented an excellent predictive ability. Furthermore, the assessment of our model revealed that protein diffusion in PSBMA hydrogel would be affected by the physical properties of the protein and the PSBMA network. It was also confirmed that the diffusion behaviors of protein in zwitterionic hydrogels can be adjusted by changing the cross-linking density of the hydrogel and the ionic strength of the swelling medium. Our model is expected to possess accurate predictive ability for the diffusion coefficient of solute in hydrogel, which will be widely used in the biomedical field.
Assuntos
Difusão , Hidrogel de Polietilenoglicol-Dimetacrilato/química , Imunoglobulina G/química , Metacrilatos/química , Muramidase/química , Soroalbumina Bovina/química , Animais , Bovinos , Modelos Moleculares , Muramidase/metabolismoRESUMO
Stem cell implantation strategy has exhibited potential to treat the myocardial infarction (MI), however, the low retention and survival limit their applications due to the reactive oxygen species (ROS) microenvironment after MI. In this study, the fullerenol nanoparticles are introduced into alginate hydrogel to create an injectable cell delivery vehicle with antioxidant activity. Results suggest that the prepared hydrogels exhibit excellent injectable and mechanical strength. In addition, the fullerenol/alginate hydrogel can effectively scavenge the superoxide anion and hydroxyl radicals. Based on these results, the biological behaviors of brown adipose-derived stem cells (BADSCs) seeded in fullerenol/alginate hydrogel were investigated in the presence of H2O2. Results suggest that the fullerenol/alginate hydrogels have no cytotoxicity effects on BADSCs. Moreover, they can suppress the oxidative stress damage of BADSCs and improve their survival capacity under ROS microenvironment via activating the ERK and p38 pathways while inhibiting JNK pathway. Further, the addition of fullerenol can improve the cardiomyogenic differentiation of BADSCs even under ROS microenvironment. To assess its therapeutic effects in vivo, the fullerenol/alginate hydrogel loaded with BADSCs were implanted in the MI area in rats. Results suggest that the fullerenol/alginate hydrogel can effectively decrease ROS level in MI zone, improve the retention and survival of implanted BADSCs, and induce angiogenesis, which in turn promote cardiac functional recovery. Therefore, the fullerenol/alginate hydrogel can act as injectable cell delivery vehicles for cardiac repair.
Assuntos
Alginatos/uso terapêutico , Antioxidantes/uso terapêutico , Fulerenos/uso terapêutico , Hidrogéis/uso terapêutico , Infarto do Miocárdio/terapia , Transplante de Células-Tronco , Tecido Adiposo Marrom/citologia , Alginatos/administração & dosagem , Alginatos/química , Animais , Antioxidantes/administração & dosagem , Antioxidantes/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Fulerenos/administração & dosagem , Fulerenos/química , Hidrogéis/administração & dosagem , Hidrogéis/química , Injeções , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Estresse Oxidativo/efeitos dos fármacos , Ratos Sprague-Dawley , Transplante de Células-Tronco/métodos , Células-Tronco/citologia , Células-Tronco/metabolismo , Alicerces Teciduais/químicaRESUMO
Multifunctional capsules have great applications in biomedical fields. In this study, novel polysaccharide-based nanocapsules were prepared via a layer-by-layer technique using silica as the templates. The shell was constructed based on the electrostatic interactions between pectin and chitosan. The pectin-chitosan nanocapsules ((Pec/Cs)3Pec) could keep good colloidal stability within 96h in PBS solution and 48h in BSA solution. Meanwhile, the nanocapsules exhibited a high drug loading and pH-sensitive release property for doxorubicin hydrochloride. Moreover, (Pec/Cs)3Pec nanocapsules had no cytotoxicity to both human hepatocellular carcinoma cells (HepG2 cells) and mouse fibroblast cells (L929 cells). More importantly, (Pec/Cs)3Pec nanocapsules could be more easily uptaken by HepG2 cells when compared with L929 cells. In vitro anticancer activity tests indicated the carriers could effectively kill HepG2 cells. Overall, (Pec/Cs)3Pec nanocapsules have great potential as a novel anticancer drug carrier as a result of their pH-sensitivity, good colloidal stability and anticancer activity.
Assuntos
Sistemas de Liberação de Medicamentos/métodos , Nanocápsulas/química , Pectinas/química , Animais , Antineoplásicos/administração & dosagem , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Quitosana/química , Doxorrubicina/administração & dosagem , Doxorrubicina/química , Células Hep G2 , Humanos , Nanocápsulas/toxicidadeRESUMO
Three-dimensional (3D) cell encapsulation in hydrogel provides superb methods to investigate the biochemical cues in directing cellular fate and behaviors outside the organism, the primary step of which is to establish suitable "blank platform" to mimic and simplify native ECM microenvironment. In this study, zwitterionic starch-based "clickable" hydrogels were fabricated via a "copper- and light- free" Michael-type "thiol-ene" addition reaction between acylated-modified sulfobetaine-derived starch (SB-ST-A) and dithiol-functionalized poly(ethylene glycol) (PEG-SH). By incorporating antifouling SB-ST and PEG, the hydrogel system would be excellently protected from nontarget protein adsorption to act as a "blank platform". The hydrogels could rapidly gel under physiological conditions in less than 7 min. Dynamic rheology experiments suggested the stiffness of the hydrogel was close to the native tissues, and the mechanical properties as well as the gelation times and swelling behaviors could be easily tuned by varying the precursor proportions. The protein and cell adhesion assays demonstrated that the hydrogel surface could effectively resist nonspecific protein and cell adhesion. The degradation study in vitro confirmed that the hydrogel was biodegradable. A549 cells encapsulated in the hydrogel maintained high viability (up to 93%) and started to proliferate in number and extend in morphology after 2 days' culture. These results indicated the hydrogel presented here could be a potential candidate as "blank platform" for 3D cell encapsulation and biochemical cues induced cellular behavior investigation in vitro.
Assuntos
Materiais Biocompatíveis/farmacologia , Técnicas de Cultura de Células/métodos , Rastreamento de Células/métodos , Neoplasias/diagnóstico por imagem , Materiais Biocompatíveis/química , Adesão Celular/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Humanos , Hidrogéis/química , Hidrogéis/farmacologia , Neoplasias/patologia , Polietilenoglicóis/química , Polietilenoglicóis/farmacologia , Amido/químicaRESUMO
In this work, a novel starch-based zwitterionic copolymer, starch-graft-poly(sulfobetaine methacrylate) (ST-g-PSBMA), was synthesized via Atom Transfer Radical Polymerization. Starch, which formed the main chain, can be degraded completely in vivo, and the pendent segments of PSBMA endowed the copolymer with excellent protein resistance properties. This ST-g-PSBMA copolymer could self-assemble into a physical hydrogel in normal saline, and studies of the formation mechanism indicated that the generation of the physical hydrogel was driven by electrostatic interactions between PSBMA segments. The obtained hydrogels were subjected to detailed analysis by scanning electron microscopy, swelling ratio, protein resistance, and rheology tests. Toxicity and hemolysis analysis demonstrated that the ST-g-PSBMA hydrogels possess excellent biocompatibility and hemocompatibility. Moreover, the cytokine secretion assays (IL-6, TNF-α, and NO) confirmed that ST-g-PSBMA hydrogels had low potential to trigger the activation of macrophages and were suitable for in vivo biomedical applications. On the basis of these in vitro results, the ST-g-PSBMA hydrogels were implanted in SD rats. The tissue responses to hydrogel implantation and the hydrogel degradation in vivo were determined by histological analysis (Hematoxylin and eosin, Van Gieson, and Masson's Trichrome stains). The results presented in this study demonstrate that the physical cross-linking, starch-based zwitterionic hydrogels possess excellent protein resistance, low macrophage-activation properties, and good biocompatibility, and they are a promising candidate for an in vivo biomedical application platform.
Assuntos
Materiais Biocompatíveis/química , Hidrogéis/química , Hidrogéis/farmacologia , Macrófagos/efeitos dos fármacos , Amido/química , Amido/farmacologia , Animais , Materiais Biocompatíveis/síntese química , Materiais Biocompatíveis/farmacologia , Materiais Biocompatíveis/normas , Sobrevivência Celular/efeitos dos fármacos , Metacrilatos , Polímeros , Ratos , Ratos Sprague-Dawley , Amido/ultraestruturaRESUMO
Over the last few decades, nanoparticles have been emerging as useful means to improve the therapeutic efficacy of drug delivery and medical diagnoses. However, the heterogeneity and complexity of blood as a medium is a fundamental problem; large amounts of protein can be adsorbed onto the surface of nanoparticles and cause their rapid clearance before reaching their target sites, resulting in the failure of drug delivery. To overcome this challenge, we present a rationally designed starch derivative (SB-ST-OC) with both a superhydrophilic moiety of zwitterionic sulfobetaine (SB) and a hydrophobic segment of octane (OC) as functional groups, which can self-assemble into "stealth" micelles (SSO micelles). The superhydrophilic SB kept the micelles stable against aggregation in complex media and imbued them with "stealth" properties, eventually extending their circulation time in blood. In stability and hemolysis tests the SSO micelles showed excellent protein resistance properties and hemocompatibility. Moreover, a phagocytosis test and cytokine secretion assay confirmed that the SSO micelles had less potential to trigger the activation of macrophages and were more suitable as a drug delivery candidate in vivo. On the basis of these results, doxorubicin (DOX), a hydrophobic drug, was used to investigate the potential application of this novel starch derivative in vivo. The results of the pharmacokinetic study showed that the values of the plasma area under the concentration curve (AUC) and elimination half-life (T1/2) of the SSO micelles were higher than those of micelles without SB modifications. In conclusion, the combination of excellent protein resistance, lower macrophage activation, and longer circulation time in vivo makes this synthesized novel starch derivative a promising candidate as a hydrophobic drug carrier for long-term circulation in vivo.
Assuntos
Doxorrubicina/administração & dosagem , Sistemas de Liberação de Medicamentos , Nanopartículas/administração & dosagem , Neoplasias/tratamento farmacológico , Doxorrubicina/química , Humanos , Interações Hidrofóbicas e Hidrofílicas , Macrófagos/efeitos dos fármacos , Micelas , Nanopartículas/química , Neoplasias/patologia , Polímeros/administração & dosagem , Polímeros/química , Amido/químicaRESUMO
Non-fouling materials bind water molecules via either hydrogen bonding or ionic solvation to form a hydration layer which is responsible for their resistance to protein adsorption. Three ionic starch-based polymers, namely a cationic starch (C-Starch), an anionic starch (A-Starch) and a zwitterionic starch (Z-Starch), were synthesized via etherification reactions to incorporate both hydrogen bonding and ionic solvation hydration groups into one molecule. Further, C-, A- and Z-Starch hydrogels were prepared via chemical crosslinking. The non-fouling properties of these hydrogels were tested with different proteins in solutions with different ionic strengths. The C-Starch hydrogel had low protein resistance at all ionic strengths; the A-Starch hydrogel resisted protein adsorption at ionic strengths of more than 10mM; and the Z-Starch hydrogel resisted protein adsorption at all ionic strengths. In addition, the A- and Z-Starch hydrogels both resisted cell adhesion. This work provides a new path for developing non-fouling materials using the integration of polysaccharides with anionic or zwitterionic moieties to regulate the protein resistance of materials.