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1.
Angew Chem Int Ed Engl ; 59(50): 22378-22381, 2020 12 07.
Artículo en Inglés | MEDLINE | ID: mdl-32866343

RESUMEN

Inspired by the amino acid composition of natural protein surfaces, we developed a zwitterionic cloak containing multi-layers of short alternating glutamic acid and lysine (EK) peptides as a facile, highly effective and low-immunogenicity approach for the protection and delivery of biotherapeutics. Each EK layer grafted to proteins provides multiple times of new lysine reaction sites for the growth of subsequent EK layers. This unique design allows EK peptides to achieve high coating density on proteins, overcoming the limitation of traditional conjugation strategies that rely on the number of innate lysine groups. A triple-layer EK cloak manifests to successfully eliminate the specific and non-specific interactions of protected asparaginase with biological media while prolong the drug circulation time and significantly mitigate its immunogenicity in vivo, suggesting an EK peptide cloak as a promising approach to improve the safety and efficacy of biotherapeutics.


Asunto(s)
Ácido Glutámico/química , Lisina/química , Péptidos/química , Proteínas/química , Propiedades de Superficie
2.
Langmuir ; 35(5): 1864-1871, 2019 02 05.
Artículo en Inglés | MEDLINE | ID: mdl-30119608

RESUMEN

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.

3.
Langmuir ; 35(5): 1544-1551, 2019 02 05.
Artículo en Inglés | MEDLINE | ID: mdl-30265550

RESUMEN

Here, we report a simple yet effective surface-modification approach to imparting hydrophobic surfaces with superhydrophilicity using ultralow fouling/functionalizable carboxybetaine (CB) copolymers via a dip-coating technique. A new series of CB random copolymers with varying amphiphilicities were synthesized and coated on hydrophobic polypropylene (PP) and polystyrene (PS) surfaces. The nonfouling capability of each coating was screened by an enzyme-linked immunosorbent assay (ELISA) and further comprehensively assessed against 100% human serum by a Micro BCA protein assay kit. The random copolymer containing ∼30 mol % CB units showed superhydrophilicity with the highest air contact angle of more than 165° in DI water and the best nonfouling capability against 100% human blood serum. Surfaces of a 96-well plate coated with the optimal CB random copolymer had a significantly better nonfouling capability than those of a commercial 96-well plate with an ultralow attachment surface. The adhesion of mouse embryonic fibroblast cells (NIH3T3) was completely inhibited on surfaces coated with CB random copolymers. Furthermore, the optimal nonfouling CB copolymer surface was functionalized with an antigen via covalent bonding where its specific interactions with its antibody were verified. Thus, this CB random copolymer is capable of imparting both ultralow fouling and functionalizable capabilities to hydrophobic surfaces for blood-contacting devices.


Asunto(s)
Resinas Acrílicas/química , Incrustaciones Biológicas/prevención & control , Compuestos de Amonio Cuaternario/química , Resinas Acrílicas/síntesis química , Resinas Acrílicas/metabolismo , Adsorción , Animales , Proteínas Sanguíneas/metabolismo , Humanos , Ratones , Células 3T3 NIH , Polipropilenos/química , Poliestirenos/química , Unión Proteica , Compuestos de Amonio Cuaternario/síntesis química , Compuestos de Amonio Cuaternario/metabolismo
4.
Angew Chem Int Ed Engl ; 58(8): 2433-2436, 2019 02 18.
Artículo en Inglés | MEDLINE | ID: mdl-30632270

RESUMEN

Although PEGylation reduces the immunogenicity of protein drugs to some extent, its limitations for highly immunogenic biotherapeutics have been demonstrated. Herein, a proactive strategy to alleviate the development of anti-drug antibodies (ADAs) against protein drugs by immunomodulatory bioconjugation is reported. Rapamycin was conjugated to a PEGylated protein therapeutic via a cleavable disulfide linker. The conjugated rapamycin can be released from the bioconjugate and prevent immune responses once the bioconjugate is uptaken by antigen-presenting cells. The immunomodulatory bioconjugate significantly reduced the titers of ADAs compared with a PEGylated protein. The inhibition of immune responses was specific to the conjugated antigen, avoiding systemic immune suppression and the risk of increased susceptibility to infections. The reported approach breaks the limitations of PEGylation by the proactive prevention of ADAs.


Asunto(s)
Anticuerpos/inmunología , Inmunomodulación , Anticuerpos/química , Reacciones Antígeno-Anticuerpo , Antígenos/inmunología , Humanos , Modelos Moleculares , Conformación Molecular , Oxidación-Reducción
5.
Proc Natl Acad Sci U S A ; 112(39): 12046-51, 2015 Sep 29.
Artículo en Inglés | MEDLINE | ID: mdl-26371311

RESUMEN

Advances in protein therapy are hindered by the poor stability, inadequate pharmacokinetic (PK) profiles, and immunogenicity of many therapeutic proteins. Polyethylene glycol conjugation (PEGylation) is the most successful strategy to date to overcome these shortcomings, and more than 10 PEGylated proteins have been brought to market. However, anti-PEG antibodies induced by treatment raise serious concerns about the future of PEGylated therapeutics. Here, we demonstrate a zwitterionic polymer network encapsulation technology that effectively enhances protein stability and PK while mitigating the immune response. Uricase modified with a comprehensive zwitterionic polycarboxybetaine (PCB) network exhibited exceptional stability and a greatly prolonged circulation half-life. More importantly, the PK behavior was unchanged, and neither anti-uricase nor anti-PCB antibodies were detected after three weekly injections in a rat model. This technology is applicable to a variety of proteins and unlocks the possibility of adopting highly immunogenic proteins for therapeutic or protective applications.


Asunto(s)
Geles/química , Nanomedicina/métodos , Proteínas/química , Proteínas/uso terapéutico , Animales , Betaína/química , Geles/farmacocinética , Geles/uso terapéutico , Semivida , Estabilidad Proteica , Proteínas/farmacocinética , Ratas , Urato Oxidasa/química
6.
Angew Chem Int Ed Engl ; 57(17): 4527-4531, 2018 04 16.
Artículo en Inglés | MEDLINE | ID: mdl-29436098

RESUMEN

While hydrophobic nanoparticles (NPs) have been long recognized to boost the immune activation, whether hydrophilic NPs modulate an immune system challenged by immune stimulators and how their hydrophilic properties may affect the immune response is still unclear. To answer this question, three polymers, poly(ethylene glycol) (PEG), poly(sulfobetaine) (PSB) and poly(carboxybetaine) (PCB), which are commonly considered hydrophilic, are studied in this work. For comparison, nanogels with uniform size and homogeneous surface functionalities were made from these polymers. Peripheral blood mononuclear cells (PBMCs) stimulated by lipopolysaccharide (LPS) and an LPS-induced lung inflammation murine model were used to investigate the influence of nanogels on the immune system. Results show that the treatment of hydrophilic nanogels attenuated the immune responses elicited by LPS both in vitro and in vivo. Moreover, we found that PCB nanogels, which have the strongest hydration and the lowest non-specific protein binding, manifested the best performance in alleviating the immune activation, followed by PSB and PEG nanogels. This reveals that the immunomodulatory effect of hydrophilic materials is closely related to their hydration characteristics and their ability to resist non-specific binding in complex media.


Asunto(s)
Inflamación/inmunología , Pulmón/inmunología , Nanopartículas/química , Polímeros/química , Animales , Modelos Animales de Enfermedad , Interacciones Hidrofóbicas e Hidrofílicas , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/inmunología , Lipopolisacáridos/farmacología , Pulmón/efectos de los fármacos , Ratones
7.
Angew Chem Int Ed Engl ; 57(42): 13873-13876, 2018 10 15.
Artículo en Inglés | MEDLINE | ID: mdl-30156051

RESUMEN

Poly(ethylene glycol) (PEG) conjugation has been the gold standard to ameliorate the pharmacokinetic (PK) and immunological profiles of proteins. PEG polymer does become immunogenic once attached to proteins, evoking PEG-specific antibody (Ab) responses. The anti-PEG Abs could cause PEGylated biologic treatments to fail and even result in lethal adverse reactions. Thus the zwitterionic poly(carboxybetaine) (PCB) has been introduced as a PEG substitute for protein modification. Addressed herein is anti-polymer Ab induction by conjugating PEG and PCB polymers to a series of carrier proteins with escalating immunogenicity. Results indicate that titers of PEG-specific Abs were quantitatively correlated to the immunogenicity of carrier proteins, whereas the generation of PCB-specific Abs was minimal and insensitive to increased protein immunogenicity. This work provides insight into the immunological properties of PEG and PCB and has far-reaching implications for the development of polymer-protein conjugates.


Asunto(s)
Anticuerpos/inmunología , Polietilenglicoles/farmacología , Animales , Ensayo de Inmunoadsorción Enzimática , Ratones , Ratones Endogámicos C57BL
8.
Angew Chem Int Ed Engl ; 57(26): 7743-7747, 2018 06 25.
Artículo en Inglés | MEDLINE | ID: mdl-29707870

RESUMEN

The commonly used "stealth material" poly(ethylene glycol) (PEG) effectively promotes the pharmacokinetics of therapeutic cargos while reducing their immune response. However, recent studies have suggested that PEG could induce adverse reactions, including the emergence of anti-PEG antibodies and tissue histologic changes. An alternative stealth material with no or less immunogenicity and organ toxicity is thus urgently needed. We designed a polypeptide with high zwitterion density (PepCB) as a stealth material for therapeutics. Neither tissue histological changes in liver, kidney, or spleen, nor abnormal behavior, sickness or death was induced by the synthesized polymer after high-dosage administration for three months in rats. When conjugated to a therapeutic protein uricase, the uricase-PepCB bioconjugate showed significantly improved pharmacokinetics and immunological properties compared with uricase-PEG conjugates.


Asunto(s)
Sistemas de Liberación de Medicamentos , Péptidos/administración & dosificación , Animales , Relación Dosis-Respuesta a Droga , Semivida , Interacciones Hidrofóbicas e Hidrofílicas , Iones , Riñón/efectos de los fármacos , Riñón/patología , Hígado/efectos de los fármacos , Hígado/patología , Péptidos/efectos adversos , Péptidos/química , Péptidos/inmunología , Ratas Sprague-Dawley , Bazo/efectos de los fármacos , Bazo/patología , Urato Oxidasa/administración & dosificación , Urato Oxidasa/inmunología , Urato Oxidasa/farmacocinética
9.
Anal Chem ; 89(16): 8217-8222, 2017 08 15.
Artículo en Inglés | MEDLINE | ID: mdl-28727918

RESUMEN

Pre-existing and induced anti-poly(ethylene glycol) (PEG) antibodies (abs) have been shown to be related with limitation of therapeutic efficacy and reduction in tolerance of several therapeutic agents. However, the current methods to detect anti-PEG abs are tedious and usually lack quantification. A facile, rapid, sensitive, and reliable technique to detect anti-PEG abs is highly desired in both research and clinic settings. In this work, we have presented a surface plasmon resonance (SPR) biosensor technique for the detection of anti-PEG abs and compared three PEG surface chemistries. Methoxy-PEG (mPEG) 5k was found to have the best performance. The detection of anti-PEG abs directly from diluted blood serum was achieved within 40 min. Detection sensitivity is as good as or better than enzyme-linked immunosorbent assay (ELISA). Furthermore, different antibody isotypes can be quantitatively differentiated by adopting secondary antibodies. A pilot study has been performed to analyze clinical blood samples using this technology, demonstrating its potential as a convenient and powerful method to prescreen and monitor anti-PEG abs in the patients before or after they receive treatment with PEG-containing drugs.


Asunto(s)
Anticuerpos/sangre , Técnicas Biosensibles/métodos , Polietilenglicoles/metabolismo , Resonancia por Plasmón de Superficie/métodos , Animales , Anticuerpos/inmunología , Humanos , Límite de Detección , Metacrilatos/química , Proyectos Piloto , Polietilenglicoles/química , Ratas , Resonancia por Plasmón de Superficie/instrumentación
10.
Anal Chem ; 89(20): 10999-11004, 2017 10 17.
Artículo en Inglés | MEDLINE | ID: mdl-28921971

RESUMEN

Cellulose paper is an ideal diagnostic platform for low-cost, easily disposable and lightweight implementation, but requires surface modification to achieve detection with high sensitivity and specificity in complex media. In this work, a polymer-catechol conjugate containing a superhydrophilic nonfouling poly(carboxylbetaine) (pCB) and four surface-binding l-3,4-dihydroxyphenylalanine (DOPA) groups, pCB-(DOPA)4, were applied onto a paper-based sensor surface via a simple "graft-to" immersion process to render the surface with both nonfouling and protein functionalizable properties. This dip-coating technique is effective, convenient and robust as compared to the "graft-from" techniques reported previously with similar nonfouling properties. The coated paper sensor showed both increased analyte diffusion rate and improved sensitivity of glucose detection in human blood serum. The capability of pCB-(DOPA)4-modified paper sensor for specific antigen-antibody detection was demonstrated via the covalent immobilization of bovine serum albumin antibody (anti-BSA) and fibrinogen antibody (anti-Fg) onto the pCB-coated surface via simple 1-ethyl-3-(3-(dimethylamino)propyl)-carbodiimide and N-hydroxysuccinimide (EDC/NHS) chemistry.


Asunto(s)
Técnicas Biosensibles/métodos , Dihidroxifenilalanina/química , Papel , Polímeros/química , Animales , Anticuerpos Inmovilizados/química , Anticuerpos Inmovilizados/inmunología , Reacciones Antígeno-Anticuerpo , Glucemia/análisis , Bovinos , Fibrinógeno/inmunología , Humanos , Inmunoensayo , Albúmina Sérica Bovina/inmunología , Succinimidas/química
11.
Langmuir ; 33(42): 11264-11269, 2017 10 24.
Artículo en Inglés | MEDLINE | ID: mdl-28850239

RESUMEN

The development of nonfouling zwitterionic materials has a wide range of biomedical and engineering applications. This work delineates the design and synthesis of a new zwitterionic material based on a naturally occurring compatible solute, ectoine, which is known to possess additional protective properties that stabilize even whole cells against ultraviolet radiation or cytotoxins. These properties and applications of ectoine inspire us to design a functional monomer containing the natural zwitterion moiety of ectoine imparting nonfouling properties and the methacrylate moiety for polymerization. The synthesis route designed for the ectoine methacrylate monomer is simple with a high yield, which is characterized by nuclear magnetic resonance spectroscopy and mass spectrometry. After monomer synthesis, we have prepared a poly(ectoine) hydrogel via thermal polymerization. The equilibrium water content, degree of cross-linking, mechanical strength, and nonfouling properties are determined for polyectoine hydrogels with different cross-linking conditions. Poly(ectoine) hydrogels are shown to have highly hydrated and excellent nonfouling properties and can be considered to be a promising biomaterial.


Asunto(s)
Aminoácidos Diaminos/síntesis química , Adsorción , Hidrogeles , Rayos Ultravioleta
12.
Pept Sci (Hoboken) ; 113(3): e24199, 2021 May.
Artículo en Inglés | MEDLINE | ID: mdl-35859761

RESUMEN

HYD1 is an all D-amino acid linear 10-mer peptide that was discovered by one-bead-one-compound screening. HYD1 has five hydrophobic amino acids flanked by polar amino acids. Alanine scanning studies showed that alternating hydrophobic amino acid residues and N- and C-terminal lysine side chains were contributors to the biological activity of the linear 10-mer analogs. This observation led us to hypothesize that display of the hydrophobic pentapeptide sequence of HYD1 in a cyclic beta-hairpin-like scaffold could lead to better bioavailability and biological activity. An amphipathic pentapeptide sequence was used to form an antiparallel strand and those strands were linked via dipeptide-like sequences selected to promote ß-turns. Early cyclic analogs were more active but otherwise mimicked the biological activity of the linear HYD1 peptide. The cyclic peptidomimetics were synthesized using standard Fmoc solid phase synthesis to form linear peptides, followed by solution phase or on-resin cyclization. SAR studies were carried out with an aim to increase the potency of these drug candidates for the killing of multiple myeloma cells in vitro. The solution structures of 1, 5, and 10 were elucidated using NMR spectroscopy. 1H NMR and 2D TOCSY studies of these peptides revealed a downfield Hα proton chemical shift and 2D NOE spectral analysis consistent with a ß-hairpin-like structure.

13.
Sci Adv ; 7(1)2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-33523839

RESUMEN

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.

14.
ACS Appl Mater Interfaces ; 12(15): 17571-17582, 2020 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-32204591

RESUMEN

Poly(hydroxymethylated-3,4-ethylenedioxythiophene):polystyrene sulfonate (PEDOT-MeOH:PSS) conducting polymers are synthesized and incorporated in inverted structured perovskite solar cells (PVSCs) as hole transport materials. The highest occupied molecular orbital of PEDOT-MeOH is lowered by adding a hydroxymethyl (-MeOH) functional group to ethylenedioxythiophene (EDOT), and thus, the work function of PEDOT-MeOH:PSS is increased. Additionally, hydrogen bonding can be formed among EDOT-MeOH monomers and between EDOT-MeOH monomers and sulfate groups on PSS, which promotes PEDOT-MeOH chain growth and enhances PSS doping. The electronic, microstructural, and surface morphological properties of PEDOT-MeOH:PSS are modified by changing the amounts of PSS and the ferric oxidizing agent used in the polymerization and by adding ethylene glycol in the postsynthesis treatment. The PVSCs based on ethylene-glycol-treated PEDOT-MeOH:PSS overperform the PVSCs based on commercial PEDOT:PSS because of the better energetic alignment and the enhancement of PEDOT-MeOH:PSS electrical conductivity. This work opens the way to develop new hole transport materials for highly efficient inverted PVSCs.

15.
Sci Adv ; 6(22): eaba0754, 2020 05.
Artículo en Inglés | MEDLINE | ID: mdl-32523997

RESUMEN

Superhydrophilic zwitterionic polymers are a class of nonfouling materials capable of effectively resisting any nonspecific interactions with biological systems. We designed here a functional zwitterionic polymer that achieves a trade-off between nonspecific interactions providing the nonfouling property and a specific interaction for bioactive functionality. Built from phosphoserine, an immune-signaling molecule in nature, this zwitterionic polymer exhibits both nonfouling and immunomodulatory properties. Its conjugation to uricase is shown to proactively eradicate all unwanted immune response, outperforming the zwitterionic polymers. On the other hand, this polymer could significantly prolong the half-life of protein drugs in vivo, overcoming the innate drawback of phosphoserine in inducing accelerated clearance. Our demonstration of a nonfouling zwitterionic material with built-in immunomodulatory functionality provides new insights into the fundamental design of biomaterials, as well as far-reaching implications for broad applications such as drug delivery, implants, and cell therapy.

16.
ACS Appl Mater Interfaces ; 12(37): 41026-41037, 2020 Sep 16.
Artículo en Inglés | MEDLINE | ID: mdl-32876425

RESUMEN

Protein and cell interactions on implanted, blood-contacting medical device surfaces can lead to adverse biological reactions. Medical-grade poly(vinyl chloride) (PVC) materials have been used for decades, particularly as blood-contacting tubes and containers. However, there are numerous concerns with their performance including platelet activation, complement activation, and thrombin generation and also leaching of plasticizers, particularly in clinical applications. Here, we report a surface modification method that can dramatically prevent blood protein adsorption, human platelet activation, and complement activation on commercial medical-grade PVC materials under various test conditions. The surface modification can be accomplished through simple dip-coating followed by light illumination utilizing biocompatible polymers comprising zwitterionic carboxybetaine (CB) moieties and photosensitive cross-linking moieties. This surface treatment can be manufactured routinely at small or large scales and can impart to commercial PVC materials superhydrophilicity and nonfouling capability. Furthermore, the polymer effectively prevented leaching of plasticizers out from commercial medical-grade PVC materials. This coating technique is readily applicable to many other polymers and medical devices requiring surfaces that will enhance performance in clinical settings.


Asunto(s)
Materiales Biocompatibles/química , Plastificantes/química , Polímeros/química , Adsorción , Animales , Ratones , Estructura Molecular , Células 3T3 NIH , Tamaño de la Partícula , Procesos Fotoquímicos , Polímeros/síntesis química , Propiedades de Superficie
17.
Acta Biomater ; 109: 51-60, 2020 06.
Artículo en Inglés | MEDLINE | ID: mdl-32251778

RESUMEN

The shelf-life of human platelets preserved in vitro for therapeutic transfusion is limited because of bacterial contamination and platelet storage lesion (PSL). The PSL is the predominant factor and limiting unfavorable interactions between the platelets and the non-biocompatible storage bag surfaces is the key to alleviate PSL. Here we describe a surface modification method for biocompatible platelet storage bags that dramatically extends platelet shelf-life beyond the current US Food and Drug Administration (FDA) standards of 5 days. The surface coating of the bags can be achieved through a simple yet effective dip-coating and light-irradiation method using a biocompatible polymer. The biocompatible polymers with tunable functional groups can be routinely fabricated at any scale and impart super-hydrophilicity and non-fouling capability on commercial hydrophobic platelet storage bags. As critical parameters reflecting the platelets quality, the activation level and binding affinity with von Willebrand factor (VWF) of the platelets stored in the biocompatible platelet bags at 8 days are comparable with those in the commercial bags at 5 days. This technique also demonstrates promise for a wide range of medical and engineering applications requiring biocompatible surfaces. STATEMENT OF SIGNIFICANCE: Current standard platelet preservation techniques agitate platelets at room temperature (20-24 °C) inside a hydrophobic (e.g., polyvinyl chloride (PVC)) storage bag, thereby allowing preservation of platelets only for 5 days. A key factor leading to quality loss is the unfavorable interaction between the platelets and the non-biocompatible storage bag surfaces. Here, a surface modification method for biocompatible platelet storage bags has been created to dramatically extend platelet shelf-life beyond the current FDA standards of 5 days. The surface coating of the bags can be achieved via a simple yet effective dip-coating and light-irradiation method using a carboxybetaine polymer. This technique is also applicable to many other applications requiring biocompatible surfaces.


Asunto(s)
Resinas Acrílicas/química , Plaquetas/efectos de los fármacos , Conservación de la Sangre/métodos , Materiales Biocompatibles Revestidos/química , Compuestos de Amonio Cuaternario/química , Animales , Adhesión Bacteriana/efectos de los fármacos , Incrustaciones Biológicas/prevención & control , Conservación de la Sangre/instrumentación , Humanos , Ratones , Células 3T3 NIH , Pseudomonas aeruginosa/efectos de los fármacos , Staphylococcus epidermidis/efectos de los fármacos
18.
Sci Adv ; 5(6): eaaw9562, 2019 06.
Artículo en Inglés | MEDLINE | ID: mdl-31214655

RESUMEN

Materials that resist nonspecific protein adsorption are needed for many applications. However, few are able to achieve ultralow fouling in complex biological milieu. Zwitterionic polymers emerge as a class of highly effective ultralow fouling materials due to their superhydrophilicity, outperforming other hydrophilic materials such as poly(ethylene glycol). Unfortunately, there are only three major classes of zwitterionic materials based on poly(phosphorylcholine), poly(sulfobetaine), and poly(carboxybetaine) currently available. Inspired by trimethylamine N-oxide (TMAO), a zwitterionic osmolyte and the most effective protein stabilizer, we here report TMAO-derived zwitterionic polymers (PTMAO) as a new class of ultralow fouling biomaterials. The nonfouling properties of PTMAO were demonstrated under highly challenging conditions. The mechanism accounting for the extraordinary hydration of PTMAO was elucidated by molecular dynamics simulations. The discovery of PTMAO polymers demonstrates the power of molecular understanding in the design of new biomimetic materials and provides the biomaterials community with another class of nonfouling zwitterionic materials.


Asunto(s)
Materiales Biocompatibles/química , Incrustaciones Biológicas/prevención & control , Metilaminas/química , Polímeros/química , Adsorción , Animales , Materiales Biocompatibles/metabolismo , Materiales Biocompatibles/farmacología , Adhesión Celular/efectos de los fármacos , Humanos , Metilaminas/metabolismo , Ratones , Ratones Endogámicos C57BL , Simulación de Dinámica Molecular , Células 3T3 NIH , Polímeros/metabolismo , Polímeros/farmacología , Albúmina Sérica/química , Resonancia por Plasmón de Superficie
19.
Nat Med ; 25(10): 1566-1575, 2019 10.
Artículo en Inglés | MEDLINE | ID: mdl-31591594

RESUMEN

The ability to expand hematopoietic stem and progenitor cells (HSPCs) ex vivo is critical to fully realize the potential of HSPC-based therapies. In particular, the application of clinically effective therapies, such as cord blood transplantation, has been impeded because of limited HSPC availability. Here, using 3D culture of human HSPCs in a degradable zwitterionic hydrogel, we achieved substantial expansion of phenotypically primitive CD34+ cord blood and bone-marrow-derived HSPCs. This culture system led to a 73-fold increase in long-term hematopoietic stem cell (LT-HSC) frequency, as demonstrated by limiting dilution assays, and the expanded HSPCs were capable of hematopoietic reconstitution for at least 24 weeks in immunocompromised mice. Both the zwitterionic characteristics of the hydrogel and the 3D format were important for HSPC self-renewal. Mechanistically, the impact of 3D zwitterionic hydrogel culture on mitigating HSPC differentiation and promoting self-renewal might result from an inhibition of excessive reactive oxygen species (ROS) production via suppression of O2-related metabolism. HSPC expansion using zwitterionic hydrogels has the potential to facilitate the clinical application of hematopoietic-stem-cell therapies.


Asunto(s)
Diferenciación Celular/efectos de los fármacos , Tratamiento Basado en Trasplante de Células y Tejidos , Células Madre Hematopoyéticas/citología , Hidrogeles/farmacología , Animales , Antígenos CD34/metabolismo , Células de la Médula Ósea/citología , Células de la Médula Ósea/metabolismo , Técnicas de Cultivo de Célula , Proliferación Celular/efectos de los fármacos , Técnicas de Cocultivo , Sangre Fetal/citología , Sangre Fetal/metabolismo , Trasplante de Células Madre Hematopoyéticas , Células Madre Hematopoyéticas/metabolismo , Humanos , Ratones , Especies Reactivas de Oxígeno/metabolismo
20.
Sci Transl Med ; 11(473)2019 01 02.
Artículo en Inglés | MEDLINE | ID: mdl-30602537

RESUMEN

Nerve agents are a class of organophosphorus compounds (OPs) that blocks communication between nerves and organs. Because of their acute neurotoxicity, it is extremely difficult to rescue the victims after exposure. Numerous efforts have been devoted to search for an effective prophylactic nerve agent bioscavenger to prevent the deleterious effects of these compounds. However, low scavenging efficiency, unfavorable pharmacokinetics, and immunological problems have hampered the development of effective drugs. Here, we report the development and testing of a nanoparticle-based nerve agent bioscavenger (nanoscavenger) that showed long-term protection against OP intoxication in rodents. The nanoscavenger, which catalytically breaks down toxic OP compounds, showed a good pharmacokinetic profile and negligible immune response in a rat model of OP intoxication. In vivo administration of the nanoscavenger before or after OP exposure in animal models demonstrated protective and therapeutic efficacy. In a guinea pig model, a single prophylactic administration of the nanoscavenger effectively prevented lethality after multiple sarin exposures over a 1-week period. Our results suggest that the prophylactic administration of the nanoscavenger might be effective in preventing the toxic effects of OP exposure in humans.


Asunto(s)
Nanopartículas/química , Agentes Nerviosos/toxicidad , Sustancias Protectoras/farmacología , Administración Intravenosa , Animales , Femenino , Cobayas , Masculino , Nanopartículas/administración & dosificación , Paraoxon/toxicidad , Sustancias Protectoras/administración & dosificación , Sustancias Protectoras/farmacocinética , Ratas Sprague-Dawley , Sarín/toxicidad , Análisis de Supervivencia , Factores de Tiempo , Distribución Tisular
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