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This study investigated the effect of polycationic and uncharged polymers (and oligomers) on the catalytic parameters and thermostability of L-asparaginase from Thermococcus sibiricus (TsA). This enzyme has potential applications in the food industry to decrease the formation of carcinogenic acrylamide during the processing of carbohydrate-containing products. Conjugation with the polyamines polyethylenimine and spermine (PEI and Spm) or polyethylene glycol (PEG) did not significantly affect the secondary structure of the enzyme. PEG contributes to the stabilization of the dimeric form of TsA, as shown by HPLC. Furthermore, neither polyamines nor PEG significantly affected the binding of the L-Asn substrate to TsA. The conjugates showed greater maximum activity at pH 7.5 and 85 °C, 10-50% more than for native TsA. The pH optima for both TsA-PEI and TsA-Spm conjugates were shifted to lower pH ranges from pH 10 (for the native enzyme) to pH 8.0. Additionally, the TsA-Spm conjugate exhibited the highest activity at pH 6.5-9.0 among all the samples. Furthermore, the temperature optimum for activity at pH 7.5 shifted from 90-95 °C to 80-85 °C for the conjugates. The thermal inactivation mechanism of TsA-PEG appeared to change, and no aggregation was observed in contrast to that of the native enzyme. This was visually confirmed and supported by the analysis of the CD spectra, which remained almost unchanged after heating the conjugate solution. These results suggest that TsA-PEG may be a more stable form of TsA, making it a potentially more suitable option for industrial use.
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Asparaginasa , Biocatálisis , Estabilidad de Enzimas , Thermococcus , Asparaginasa/química , Asparaginasa/metabolismo , Thermococcus/enzimología , Concentración de Iones de Hidrógeno , Polietilenglicoles/química , Temperatura , Proteínas Arqueales/química , Proteínas Arqueales/metabolismoRESUMEN
The combination of biomolecules and synthetic polymers provides an easy access to utilize advantages from both the synthetic world and nature. This is not only important for the development of novel innovative materials, but also promotes the application of biomolecules in various fields including medicine, catalysis, and water treatment, etc. Due to the rapid progress in synthesis strategies for polymer nanomaterials and deepened understanding of biomolecules' structures and functions, the construction of advanced polymer-based biohybrid nanostructures (PBBNs) becomes prospective and attainable. Polymerization-induced self-assembly (PISA), as an efficient and versatile technique in obtaining polymeric nano-objects at high concentrations, has demonstrated to be an attractive alternative to existing self-assembly procedures. Those advantages induce the focus on the fabrication of PBBNs via the PISA technique. In this review, current preparation strategies are illustrated based on the PISA technique for achieving various PBBNs, including grafting-from and grafting-through methods, as well as encapsulation of biomolecules during and subsequent to the PISA process. Finally, advantages and drawbacks are discussed in the fabrication of PBBNs via the PISA technique and obstacles are identified that need to be overcome to enable commercial application.
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Nanoestructuras , Polímeros , Polimerizacion , Polímeros/química , Estudios Prospectivos , Nanoestructuras/química , CatálisisRESUMEN
Oxygen-tolerant, aqueous copper-mediated polymerization approaches are combined with click chemistry in either a sequential or a simultaneous manner, to enable the synthesis of multifunctional protein-polymer conjugates. Propargyl acrylate (PgA) and propargyl methacrylate (PgMA) grafting from a bovine serum albumin (BSA) macroinitiator is thoroughly optimized to synthesize chemically addressable BSA-poly(propargyl acrylate) and BSA-poly(propargyl methacrylate) respectively. The produced multifunctional bioconjugates bear pendant terminal 1-alkynes which can be readily post-functionalized via both [3+2] Huisgen cycloaddition and thiol-yne click chemistry under mild reaction conditions. Simultaneous oxygen-tolerant, aqueous copper-catalyzed polymerization, and click chemistry mediate the in situ multiple chemical tailoring of biomacromolecules in excellent yields.
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Química Clic , Cobre , Cobre/química , Polimerizacion , Polímeros/química , Albúmina Sérica Bovina , Acrilatos , Metacrilatos , Alquinos/química , Azidas/química , Reacción de CicloadiciónRESUMEN
The emergence and growth of bacterial resistance to antibiotics poses an enormous threat to humanity in the future. In this regard, the discovery of new antibiotics and the improvement of existing ones is a priority task. In this study, we proposed the synthesis of new polymeric conjugates of polymyxin B, which is a clinically approved but limited-use peptide antibiotic. In particular, three carboxylate-bearing polymers and one synthetic glycopolymer were selected for conjugation with polymyxin B (PMX B), namely, poly(α,L-glutamic acid) (PGlu), copolymer of L-glutamic acid and L-phenylalanine (P(Glu-co-Phe)), copolymer of N-vinyl succinamic acid and N-vinylsuccinimide (P(VSAA-co-VSI)), and poly(2-deoxy-2-methacrylamido-D-glucose) (PMAG). Unlike PGlu and PMAG, P(Glu-co-Phe) and P(VSAA-co-VSI) are amphiphilic and form nanoparticles in aqueous media. A number of conjugates with different polymyxin B loading were synthesized and characterized. In addition, the complex conjugates of PGLu or PMAG with polymyxin B and deferoxamine (siderophore) were obtained. A release of PMX B from Schiff base and amide-linked polymer conjugates was studied in model buffer media with pH 7.4 and 5.8. In both cases, a more pronounced release was observed under slightly acidic conditions. The cytotoxicity of free polymers and PMX B as well as their conjugates was examined in human embryonic kidney cells (HEK 293T cell line). All conjugates demonstrated reduced cytotoxicity compared to the free antibiotic. Finally, the antimicrobial efficacy of the conjugates against Pseudomonas aeruginosa was determined and compared. The lowest values of minimum inhibitory concentrations (MIC) were observed for polymyxin B and polymyxin B/deferoxamine conjugated with PMAG. Among the polymers tested, PMAG appears to be the most promising carrier for delivery of PMX B in conjugated form due to the good preservation of the antimicrobial properties of PMX B and the ability of controlled drug release.
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Deferoxamina , Polimixina B , Humanos , Polimixina B/farmacología , Ácido Glutámico , Antibacterianos/farmacología , Polímeros/químicaRESUMEN
BACKGROUND: Apoptotic cells' phosphoserine (PS) groups have a significant immunosuppressive effect. They inhibit proinflammatory signals by interacting with various immune cells, including macrophages, dendritic cells, and CD4+ cells. Previously, we synthesized PS-group-immobilized polymers and verified their immunomodulatory effects. Despite its confirmed immunomodulatory potential, the PS group has not been considered as a payload for antibody-drug conjugates (ADCs) in a targeted anti-inflammatory approach. AIM: We conducted this research to introduce an apoptotic-cell-inspired antibody-drug conjugate for effective immunomodulation. METHOD: Poly(2-hydroxyethyl methacrylate-co-2-methacryloyloxyethyl phosphorylserine) (p(HEMA-co-MPS)) was synthesized as a payload using RAFT polymerization, and goat anti-mouse IgG was selected as a model antibody, which was conjugated with the synthesized p(HEMA-co-MPS) via 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide/N-Hydroxysuccinimide (EDC/NHS) reaction. The antibody-binding affinity, anti-inflammatory potential, and cytotoxicity measurements were evaluated. RESULTS: We successfully synthesized ADCs with a significant anti-inflammatory effect and optimized the antibody-polymer ratio to achieve the highest antibody-binding affinity. CONCLUSION: We successfully introduced p(HEMA-co-MPS) to IgG without decreasing the anti-inflammatory potential of the polymer while maintaining its targeting ability. We suggest that the antibody-polymer ratio be appropriately adjusted for effective therapy. In the future, this technology can be applied to therapeutic antibodies, such as Tocilizumab or Abatacept.
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Inmunoconjugados , Inmunoconjugados/farmacología , Inmunoconjugados/uso terapéutico , Polímeros , Inmunoglobulina G , AntiinflamatoriosRESUMEN
In this study, we addressed the limitations of conventional enzyme-polymer-conjugate-based Pickering emulsions for interfacial biocatalysis, which traditionally suffer from nonspecific and uncontrollable conjugation positions that can impede catalytic performance. By introducing a non-canonical amino acid (ncAA) at a specific site on target enzymes, we enabled precise polymer-enzyme conjugation. These engineered conjugates then acted as biocatalytically active emulsifiers to stabilize Pickering emulsions, while encapsulating a cell-free protein synthesis (CFPS) system in the aqueous phase for targeted enzyme expression. The resulting cascade reaction system leveraged enzymes expressed in the aqueous phase and on the emulsion interface for optimized chemical biosynthesis. The use of the cell-free system eliminated the need for intact whole cells or purified enzymes, representing a significant advancement in biocatalysis. Remarkably, the integration of Pickering emulsion, precise enzyme-polymer conjugation, and CFPS resulted in a fivefold enhancement in catalytic performance as compared to traditional single-phase reactions. Therefore, our approach harnesses the combined strengths of advanced biochemical engineering techniques, offering an efficient and practical solution for the synthesis of value-added chemicals in various biocatalysis and biotransformation applications.
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Polímeros , Emulsiones/química , Biocatálisis , Catálisis , BiotransformaciónRESUMEN
Protein-polymer conjugates are a blooming class of hybrid systems with high biomedical potential. Despite a plethora of papers on their biomedical properties, the physical-chemical characterization of many protein-polymer conjugates is missing. Here, we evaluated the thermal stability of a set of fully-degradable polyphosphoester-protein conjugates by variable temperature circular dichroism, a common but powerful technique. We extensively describe their thermodynamic stability in different environments (in physiological buffer or in presence of chemical denaturants, e.g., acid or urea), highlighting the protective role of the polymer in preserving the protein from denaturation. For the first time, we propose a simple but effective protocol to achieve useful information on these systems in vitro, useful to screen new samples in their early stages.
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Mioglobina , Polímeros , Dicroismo Circular , Polímeros/química , Desnaturalización Proteica , Estereoisomerismo , TermodinámicaRESUMEN
The growth of microbial multidrug resistance is a problem in modern clinical medicine. Chemical modification of active pharmaceutical ingredients is an attractive strategy to improve their biopharmaceutical properties by increasing bioavailability and reducing drug toxicity. Conjugation of antimicrobial drugs with natural polysaccharides provides high efficiency of these systems due to targeted delivery, controlled drug release and reduced toxicity. This paper reports a two-step synthesis of colistin conjugates (CT) with succinyl chitosan (SucCS); first, we modified chitosan with succinyl anhydride to introduce a carboxyl function into the polymer molecule, which was then used for chemical grafting with amino groups of the peptide antibiotic CT using carbodiimide chemistry. The resulting polymeric delivery systems had a degree of substitution (DS) by CT of 3-8%, with conjugation efficiencies ranging from 54 to 100% and CT contents ranging from 130-318 µg/mg. The size of the obtained particles was 100-200 nm, and the ζ-potential varied from -22 to -28 mV. In vitro release studies at pH 7.4 demonstrated ultra-slow hydrolysis of amide bonds, with a CT release of 0.1-0.5% after 12 h; at pH 5.2, the hydrolysis rate slightly increased; however, it remained extremely low (1.5% of CT was released after 12 h). The antimicrobial activity of the conjugates depended on the DS. At DS 8%, the minimum inhibitory concentration (MIC) of the conjugate was equal to the MIC of native CT (1 µg/mL); at DS of 3 and 5%, the MIC increased 8-fold. In addition, the developed systems reduced CT nephrotoxicity by 20-60%; they also demonstrated the ability to reduce bacterial lipopolysaccharide-induced inflammation in vitro. Thus, these promising CT-SucCS conjugates are prospective for developing safe and effective nanoantibiotics.
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Quitosano , Colistina , Colistina/farmacología , Quitosano/química , Estudios Prospectivos , Sistemas de Liberación de Medicamentos , Antibacterianos/farmacología , Antibacterianos/químicaRESUMEN
This paper focuses on preliminary in vitro and in vivo testing of new bivalent folate-targeted PEGylated doxorubicin (DOX) made by modular chemo-enzymatic processes (FA2-dPEG-DOX2). A unique feature is the use of monodisperse PEG (dPEG). The modular approach with enzyme catalysis ensures exclusive γ-conjugation of folic acid, full conversion and selectivity, and no metal catalyst residues. Flow cytometry analysis showed that at 10 µM concentration, both free DOX and FA2-dPEG-DOX2 would be taken up by 99.9% of triple-negative breast cancer cells in 2 h. Intratumoral injection to mice seemed to delay tumor growth more than intravenous delivery. The mouse health status, food, water consumption, and behavior remained unchanged during the observation.
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Doxorrubicina , Ácido Fólico , Nanopartículas , Neoplasias de la Mama Triple Negativas , Animales , Línea Celular Tumoral , Doxorrubicina/química , Doxorrubicina/farmacología , Femenino , Citometría de Flujo , Ácido Fólico/química , Ácido Fólico/farmacología , Humanos , Masculino , Ratones , Ratones Desnudos , Nanopartículas/química , Nanopartículas/uso terapéutico , Neoplasias de la Mama Triple Negativas/diagnóstico , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Protein-polymer conjugates are increasingly being applied in biomedicine because of the unique combination of the biological activity of the proteins and the multifunctionality and flexibility of the polymers. However, traditional protein-polymer conjugation techniques suffer from some unavoidable drawbacks, including nonspecificity and low efficiency. In this Minireview, we discuss a new approach based on "precision conjugation" for the construction of the next-generation protein-polymer conjugates in a more controlled, more efficient, and tailorable fashion for a broad range of advanced applications. In illustrating the concept, we highlight two general methods: site-specific inâ situ growth and intrinsically disordered polypeptide fusion, with a focus on the inâ situ, efficient, and controllable formation of protein-polymer conjugates. At the end, the challenges associated with this emerging concept are further discussed.
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Polímeros/química , Proteínas/química , PolimerizacionRESUMEN
Biomolecule-polymer conjugates are constructs that take advantage of the functional or otherwise beneficial traits inherent to biomolecules and combine them with synthetic polymers possessing specially tailored properties. The rapid development of novel biomolecule-polymer conjugates based on proteins, peptides, or nucleic acids has ushered in a variety of unique materials, which exhibit functional attributes including thermo-responsiveness, exceptional stability, and specialized specificity. Key to the synthesis of new biomolecule-polymer hybrids is the use of controlled polymerization techniques coupled with either grafting-from, grafting-to, or grafting-through methodology, each of which exhibit distinct advantages and/or disadvantages. In this review, we present recent progress in the development of biomolecule-polymer conjugates with a focus on works that have detailed the use of grafting-from methods employing ATRP, RAFT, or ROMP.
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Herein, we report the photoinitiated polymerization-induced self-assembly (photo-PISA) of spherical micelles consisting of proapoptotic peptide-polymer amphiphiles. The one-pot synthetic approach yielded micellar nanoparticles at high concentrations and at scale (150â mg mL-1 ) with tunable peptide loadings up to 48â wt. %. The size of the micellar nanoparticles was tuned by varying the lengths of hydrophobic and hydrophilic building blocks. Critically, the peptide-functionalized nanoparticles imbued the proapoptotic "KLA" peptides (amino acid sequence: KLAKLAKKLAKLAK) with two key properties otherwise not inherent to the sequence: 1)â proteolytic resistance compared to the oligopeptide alone; 2)â significantly enhanced cell uptake by multivalent display of KLA peptide brushes. The result was demonstrated improved apoptosis efficiency in HeLa cells. These results highlight the potential of photo-PISA in the large-scale synthesis of functional, proteolytically resistant peptide-polymer conjugates for intracellular delivery.
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Apoptosis , Luz , Nanopartículas/química , Péptidos/química , Polímeros/química , Secuencia de Aminoácidos , Supervivencia Celular/efectos de los fármacos , Células HeLa , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Micelas , PolimerizacionRESUMEN
Typically, the morphologies of the self-assembled nanostructures from block copolymers are limited to spherical micelles, wormlike micelles and vesicles. Now, a new generation of materials with unique shape and structures, cylindrical soft matter particles (tubisomes), are obtained from the hierarchical self-assembly of cyclic peptide-bridged amphiphilic diblock copolymers. The capacity of obtained photo-responsive tubisomes as potential drug carriers is evaluated. The supramolecular tubisomes pave an alternative way for fabricating polymeric tubular structures, and will expand the toolbox for the rational design of functional hierarchical nanostructures.
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Oral application of therapeutic enzymes is a promising and non-invasive administration that improves patient compliance. However, the gastrointestinal tract poses several challenges to the oral delivery of proteins, including harsh pH conditions and digestive proteases. A promising way to stabilise enzymes during their gastrointestinal route is by modification with polymers that can provide both steric shielding and selective interaction in different digestive compartments. We give an overview of modification technologies for oral enzymes ranging from functionalisation of native proteins, to site-specific mutation and protein-polymer engineering. We specifically focus on enzymes that are active directly in the gastrointestinal lumen and not systemically absorbed. In addition, we discuss examples of microparticle and nanoparticle encapsulated enzymes for improved oral delivery. The modification of orally administered enzymes offers a broad chemical variability and may be a promising tool for enhancing their gastrointestinal stability.
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Sistemas de Liberación de Medicamentos , Enzimas/farmacología , Tracto Gastrointestinal , Nanopartículas , Ingeniería de Proteínas , Administración Oral , Estabilidad de Enzimas , Humanos , Péptido Hidrolasas , PolímerosRESUMEN
The past decade may be considered as revolutionary in the research field focused on the physiological function of macrophages. Unknown subtypes of these cells involved in pathological mechanisms were described recently, and they are considered as potential drug delivery targets. The innate ability to internalize foreign bodies exhibited by macrophages can be employed as a therapeutic strategy. The efficiency of this uptake depends on the size, shape and surface physiochemical properties of the phagocyted objects. Here, we propose a method of preparation and preliminary evaluation of drug-polymer conjugate-based microspheres for macrophage targeted drug delivery. The aim of the study was to identify crucial uptake-enhancing parameters for solid, surface modified particles. A model drug molecule-lamivudine-was conjugated with poly-ε-caprolactone via ring opening polymerization. The conjugate was utilized in a solvent evaporation method technique to form solid particles. Interactions between particles and a model rat alveolar cell line were evaluated by flow cytometry. The polymerization product was characterized by a molecular weight of 3.8 kDa. The surface of the obtained solid drug-loaded cores of a hydrodynamic diameter equal to 2.4 µm was modified with biocompatible polyelectrolytes via a layer-by-layer assembly method. Differences in the internalization efficiency of four particle batches by the model RAW 264.7 cell line suggest that particle diameter and surface hydrophobicity are the most influential parameters in terms of phagocytic uptake.
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Fármacos Anti-VIH/administración & dosificación , Caproatos/administración & dosificación , Portadores de Fármacos/química , Sistemas de Liberación de Medicamentos , Lactonas/administración & dosificación , Lamivudine/administración & dosificación , Macrófagos/metabolismo , Animales , Fármacos Anti-VIH/química , Caproatos/química , Supervivencia Celular/efectos de los fármacos , Combinación de Medicamentos , Lactonas/química , Lamivudine/química , Macrófagos/inmunología , Espectroscopía de Resonancia Magnética , Ratones , Microesferas , Fagocitosis , Polímeros/metabolismo , Células RAW 264.7 , Análisis EspectralRESUMEN
Since their discovery in 1993, interest in various aspects of cyclic peptides (CPs) has expanded rapidly. Of particular note is their potential to form artificial ion channels in lipid membranes, an attractive characteristic in supramolecular chemistry and biological research. The design and synthesis of cyclic peptide-polymer conjugates (CPPCs) that can self-assemble within lipid bilayers into nanotubes, mimicking naturally occurring membrane channels and pores, has been reported. However, methods that allow direct detection of the transport process with high levels of certainty are still lacking. This work focuses on the development of a simple but reliable approach to verify and quantify proton transport across a bilayer membrane. Giant unilamellar vesicles (GUVs) are created via the electroformation method and CPPCs are incorporated in GUV membranes at varying concentrations (0-10%). Confocal fluorescence microscopy is used to demonstrate full inclusion of fluorescein-labeled CPPCs in the GUV membranes. The pH-sensitive dye carboxyfluorescein is encapsulated within the water pool of the GUVs and used as an indicator of proton transport. This assay is versatile and can be exploited on other existing proton transporter systems, providing a consistent tool to compare their performances. It should also aid the development of novel antineoplastics and drug delivery systems.
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Canales Iónicos/química , Nanotubos/química , Péptidos Cíclicos/química , Protones , Liposomas Unilamelares/química , Transporte Iónico , Microscopía FluorescenteRESUMEN
Despite the rapid development of Pickering interfacial catalysis (PIC) at liquid-liquid interfaces with chemocatalysts, the use of unstable biocatalysts at emulsion interfaces remains a technical challenge. Herein, we present a Pickering interfacial biocatalysis (PIB) platform based on robust and recyclable enzyme-polymer conjugates that act as both catalytic sites and stabilizers at the interface of Pickering emulsions. The conjugates were prepared by growing poly(N-isopropylacrylamide) on a fragile enzyme, benzaldehyde lyase, under physiological conditions. The mild in situ conjugation process preserved the enzyme structure, and the conjugates were used to emulsify a water-organic two-phase system into a stable Pickering emulsion, leading to a significantly larger interfacial area and a 270-fold improvement in catalytic performance as compared to the unemulsified two-phase system. The PIB system could be reused multiple times. Conjugates of other enzymes were also fabricated and applied for cascade reactions.
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Peptide sciences developed dramatically as a result of routine use of solid-phase peptide synthesis and nowadays offer a rich set of well-established strategies to design and identify functional peptide sequences for advanced applications in materials sciences. Appropriate sequences for a wide range of interesting material targets, ranging from molecules to materials surfaces and internal interfaces, can be selected via combinatorial means, and sequence specificities within the resulting peptide-target interactions can be routinely investigated. Based on this understanding, macromolecular sciences can define new polymer structures that meet required functionalities or functional sequences with fully synthetic, nonpeptidic precision polymers to endeavor toward information-based design of next-generation, purpose-adapted macromolecules.
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Péptidos/síntesis química , Polímeros/síntesis química , Sustancias Macromoleculares/síntesis química , Sustancias Macromoleculares/química , Biblioteca de Péptidos , Péptidos/química , Polímeros/químicaRESUMEN
Alanine:glyoxylate aminotransferase (AGT) is a liver peroxisomal enzyme whose deficit causes the rare disorder Primary Hyperoxaluria Type I (PH1). We now describe the conjugation of poly(ethylene glycol)-co-poly(L-glutamic acid) (PEG-PGA) block-co-polymer to AGT via the formation of disulfide bonds between the polymer and solvent-exposed cysteine residues of the enzyme. PEG-PGA conjugation did not affect AGT structural/functional properties and allowed the enzyme to be internalized in a cellular model of PH1 and to restore glyoxylate-detoxification. The insertion of the C387S/K390S amino acid substitutions, known to favor interaction with the peroxisomal import machinery, reduced conjugation efficiency, but endowed conjugates with the ability to reach the peroxisomal compartment. These results, along with the finding that conjugates are hemocompatible, stable in plasma, and non-immunogenic, hold promise for the development of polypeptide-based AGT conjugates as a therapeutic option for PH1 patients and represent the base for applications to other diseases related to deficits in peroxisomal proteins.
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Sistemas de Liberación de Medicamentos , Hiperoxaluria Primaria/tratamiento farmacológico , Peroxisomas/metabolismo , Polietilenglicoles/química , Ácido Poliglutámico/análogos & derivados , Transaminasas/administración & dosificación , Transaminasas/química , Sustitución de Aminoácidos , Animales , Células CHO , Cricetulus , Terapia Enzimática , Glioxilatos/metabolismo , Humanos , Hiperoxaluria Primaria/enzimología , Hiperoxaluria Primaria/metabolismo , Modelos Moleculares , Peroxisomas/efectos de los fármacos , Transaminasas/genética , Transaminasas/farmacocinéticaRESUMEN
Polyethylene glycol (PEG) polymers are currently used in a variety of medical formulations to reduce toxicity, minimize immune interactions and improve pharmacokinetics. Despite its widespread use however, the presence of anti-PEG antibodies indicates that this polymer has the potential to be immunogenic and antigenic. Here we present an alternative polymer, poly(2-oxazoline) (POx) for stealth applications, specifically shielding of a proteinaceous nanoparticle from recognition by the immune system. Tobacco mosaic virus (TMV) was used as our testbed due to its potential for use as a nanocarrier for drug delivery and molecular imaging applications.