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Inspired by natural resources, such as peptides and carbohydrates, glycopolypeptide biopolymer has recently emerged as a new form of biopolymer being recruited in various biomedical applications. Glycopolypeptides with well-defined secondary structures and pendant glycosides on the polypeptide backbone have sparked lots of research interest and they have an innate ability to self-assemble in diverse structures. The nanostructures of glycopolypeptides have also opened up new perspectives in biomedical applications due to their stable three-dimensional structures, high drug loading efficiency, excellent biocompatibility, and biodegradability. Although the development of glycopolypeptide-based nanocarriers is well-studied, their clinical translation is still limited. The present review highlights the preparation and characterization strategies related to glycopolypeptides-based copolymers, followed by a comprehensive discussion on their biomedical applications with a specific focus on drug delivery by various stimuli-responsive (e.g., pH, redox, conduction, and sugar) nanostructures, as well as their beneficial usage in diagnosis and regenerative medicine. [Display omitted] • Glycopolypeptides with well-defined secondary structures have an innate ability to self-assemble in diverse nanostructures. • Glycopolypeptide-based nanoparticles possess high drug-loading efficiency and excellent biocompatibility. • Synthetic glycopeptides have biological properties similar to natural glycoproteins. • Stimuli-responsive controlled drug delivery has been achieved by glycopolypeptide self-assemblies. [ABSTRACT FROM AUTHOR]

Proteoglycans (PGs), also known as a viscous lubricant, is the main component of the cartilage extracellular matrix (ECM). The loss of PGs is accompanied by the chronic degeneration of cartilage tissue, which is an irreversible degeneration process that eventually develops into osteoarthritis (OA). Unfortunately, there is still no substitute for PGs in clinical treatments. Herein, we propose a new PGs analogue. The Glycopolypeptide hydrogels in the experimental groups with different concentrations were prepared by Schiff base reaction (Gel-1, Gel-2, Gel-3, Gel-4, Gel-5 and Gel-6). They have good biocompatibility and adjustable enzyme-triggered degradability. The hydrogels have a loose and porous structure suitable for the proliferation, adhesion, and migration of chondrocytes, good anti-swelling, and reduce the reactive oxygen species (ROS) in chondrocytes. In vitro experiments confirmed that the glycopolypeptide hydrogels significantly promoted ECM deposition and up-regulated the expression of cartilage-specific genes, such as type-II collagen, aggrecan, and glycosaminoglycans (sGAG). In vivo, the New Zealand rabbit knee articular cartilage defect model was established and the hydrogels were implanted to repair it, the results showed good cartilage regeneration potential. It is worth noting that the Gel-3 group, with a pore size of 122 ​± ​12 ​μm, was particularly prominent in the above experiments, and provides a theoretical reference for the design of cartilage-tissue regeneration materials in the future.

The cellular glycocalyx is involved in diverse biological phenomena in health and disease. Yet, molecular level studies have been challenged by a lack of tools to precisely manipulate this heterogeneous structure. Engineering of the cell surface using insertion of hydrophobic-terminal materials has emerged as a simple and efficient method with great promise for glycocalyx studies. However, there is a dearth of information about how the structure of the material affects membrane insertion efficiency and resulting density, the residence time of the material, or what types of cells can be utilized. Here, we examine a panel of synthetic mucin structures terminated in highly efficient cholesterylamide membrane anchors for their ability to engineer the glycocalyx of five different cell lines. We examined surface density, residence time and half-life, cytotoxicity, and the ability be passed to daughter cells. We report that this method is robust for a variety of polymeric structures, long-lasting, and well-tolerated by a variety of cell lines.

Despite clinical applications of the first‐generation tissue adhesives and hemostats, the correlation among microstructure and hemostasis of hydrogels with wound healing is less understood and it is elusive to design high‐performance hydrogels to meet worldwide growing demands in wound closure, hemostasis, and healing. Inspired by the microstructure of extracellular matrix and mussel‐mimetic chemistry, two kinds of coordinated and covalent glycopolypeptide hydrogels are fabricated, which present tunable tissue adhesion strength (14.6–83.9 kPa) and microporous structure (8–18 µm), and lower hemolysis <1.5%. Remarkably, the microporous size mainly controls the hemostasis, and those hydrogels with larger pores of 16–18 µm achieve the fastest hemostasis of ≈14 s and the lowest blood loss of ≈6% than fibrin glue and others. Moreover, both biocompatibility and hemostasis affect wound healing performance, as assessed by hemolysis, cytotoxicity, subcutaneous implantation, and hemostasis and healing assays. Importantly, the glycopolypeptide hydrogel‐treated rat‐skin defect model achieves full wound closure and regenerates thick dermis and epidermis with some hair follicles on day 14. Consequently, this work not only establishes a versatile method for constructing glycopolypeptide hydrogels with tunable adhesion and microporous structure, fast hemostasis, and superior healing functions, but also discloses a useful rationale for designing high‐performance hemostatic and healing hydrogels. [ABSTRACT FROM AUTHOR]

Carbohydrates play essential structural and biochemical roles in all living organisms. Glycopolymers are attractive as well-defined biomimetic analogs to study carbohydrate-dependent processes, and are widely applicable biocompatible materials in their own right. Glycopolypeptides have shown great promise in this area since they are closer structural mimics of natural glycoproteins than other synthetic glycopolymers and can serve as carriers for biologically active carbohydrates. This review highlights advances in the area of design and synthesis of such materials, and their biomedical applications in therapeutic delivery, tissue engineering, and beyond. Unlabelled Image [ABSTRACT FROM AUTHOR]

A lack of biological activity hinders the application of synthetic hydrogels in tissue engineering and regenerative medicine. However, the use of glycopolypeptides in hydrogel synthesis may provide the materials with the desired biological activities. Herein, we prepared three in situ-forming hydrogels from various phenol-functionalized glycopolypeptides. The gelation time, mechanical properties, degradation properties, and biocompatibility of the hydrogels were assessed. Gelation time ranged from 11 to 380 s, depending on the concentration of horseradish peroxidase. The galactose-modified polypeptide hydrogel showed the highest storage modulus with an obvious stress relaxation phenomenon. The prepared hydrogels exhibited good degradation properties and compatibility to cells and tissues. Furthermore, the rate of immune cell accumulation around the mannose-modified polypeptide hydrogel was the fastest among the hydrogels. [ABSTRACT FROM AUTHOR]

Carboxyl functional groups of poly(L-glutamic acid) (PGlu) were modified with a D-(+)-glucosamine (GlcN) by amidation using 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMTMM) as a coupling reagent. The coupling reaction was performed in aqueous medium without protection of hydroxyl functional groups of D-(+)-glucosamine. Poly(L-glutamic acid) and GlcN functionalized polyglutamates (P(Glu-GlcN)) were thoroughly characterized by 1D and 2D NMR spectroscopy and SEC-MALS to gain detailed information on their structure, composition and molar mass characteristics. The results reveal successful functionalization with GlcN through the amide bond and also to a minor extent through ester bond formation in position 1 of GlcN. In addition, a ratio between the α- and β-form of glucosamine substituent coupled to polyglutamate repeating units as well as the content of residual dimethoxy triazinyl active ester moiety in the samples were evaluated.

Amphiphilic glycopolypeptide analogues have harboured great importance in the development of targeted drug delivery systems. In this study, lactosylated pullulan-graft-arginine dendrons (LP-g-G3P) was synthesized using Huisgen azide-alkyne 1,3-dipolar cycloaddition between lactosylated pullulan and generation 3 arginine dendrons bearing Pbf and Boc groups on the periphery. Hydrophilic lactosylated pullulan was selected for amphiphilic modification, aiming at specific lectin recognition. Macromolecular structure of LP-g-G3P combined alkyl, aromatic, and peptide dendritic hydrophobic moieties and was able to self-assemble spontaneously into core-shell nanoarchitectures with small particle sizes and low polydispersity in the aqueous media, which was confirmed by CAC, DLS and TEM. Furthermore, the polyaromatic anticancer drug (doxorubicin, DOX) was selectively encapsulated in the hydrophobic core through multiple interactions with the dendrons, including π-π interactions, hydrogen bonding and hydrophobic interactions. Such multiple interactions had the merits of enhanced drug loading capacity (16.89 ± 2.41%), good stability against dilution, and excellent sustained release property. The cell viability assay presented that LP-g-G3P nanoparticles had an excellent biocompatibility both in the normal and tumor cells. Moreover, LP-g-G3P/DOX nanoparticles could be effectively internalized into the hepatoma carcinoma cells and dramatically inhibited cell proliferation. Thus, this approach paves the way to develop amphiphilic and biofunctional glycopolypeptide-based drug delivery systems. [ABSTRACT FROM AUTHOR]

Proteoglycans (PGs), also known as a viscous lubricant, is the main component of the cartilage extracellular matrix (ECM). The loss of PGs is accompanied by the chronic degeneration of cartilage tissue, which is an irreversible degeneration process that eventually develops into osteoarthritis (OA). Unfortunately, there is still no substitute for PGs in clinical treatments. Herein, we propose a new PGs analogue. The Glycopolypeptide hydrogels in the experimental groups with different concentrations were prepared by Schiff base reaction (Gel-1, Gel-2, Gel-3, Gel-4, Gel-5 and Gel-6). They have good biocompatibility and adjustable enzyme-triggered degradability. The hydrogels have a loose and porous structure suitable for the proliferation, adhesion, and migration of chondrocytes, good anti-swelling, and reduce the reactive oxygen species (ROS) in chondrocytes. In vitro experiments confirmed that the glycopolypeptide hydrogels significantly promoted ECM deposition and up-regulated the expression of cartilage-specific genes, such as type-II collagen, aggrecan, and glycosaminoglycans (sGAG). In vivo, the New Zealand rabbit knee articular cartilage defect model was established and the hydrogels were implanted to repair it, the results showed good cartilage regeneration potential. It is worth noting that the Gel-3 group, with a pore size of 122 ​± ​12 ​μm, was particularly prominent in the above experiments, and provides a theoretical reference for the design of cartilage-tissue regeneration materials in the future., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

The targeted delivery of chemotherapy drugs to tumor lesions is a major challenge for the treatment of tumors. Up until now, various polymeric nanoparticles have been explored to improve the targetability of these therapeutic drugs through passive or active targeting processes. In the design and construction of polymer nanoparticles, glycopolypeptide has shown great potential owing to its excellent targeting ability and biocompatibility. In order to enhance the antitumor effect of doxorubicin (DOX), a glycopolypeptide-based micelle (GPM) modified by α-lactose (Lac) was synthesized for targeted treatment of hepatoma. The DOX-loaded GPM (i.e., GPM/DOX) could significantly target human hepatoma (HepG2) cells and further inhibit their proliferation in vitro. Additionally, GPM/DOX exhibited a much higher drug accumulation in tumor tissue and a stronger antitumor effect in vivo than free DOX. The above results revealed that this drug delivery system provides a promising platform for the targeting therapy of hepatic cancer.

[Display omitted] Mucin glycoproteins are the major component of mucus and coat epithelial cell surfaces forming the glycocalyx. The glycocalyx and mucus are involved in the transport of nutrients, drugs, gases, and pathogens toward the cell surface. Mucins are also involved in diverse diseases such as cystic fibrosis and cancer. Due to inherent heterogeneity in native mucin structure, many synthetic materials have been designed to probe mucin chemistry, biology, and physics. Such materials include various glycopolymers, low molecular weight glycopeptides, glycopolypeptides, polysaccharides, and polysaccharide-protein conjugates. This review highlights advances in the area of design and synthesis of mucin mimic materials, and their biomedical applications in glycan binding, epithelial models of infection, therapeutic delivery, vaccine formulation, and beyond. [ABSTRACT FROM AUTHOR]

• Mucins are the major component of mucus, which hydrates and protects tissues. • Mucins are involved in lubrication, cancer, infection, and reproduction. • Artificial mucins have application in vaccines, lubricants, and anti-infectives. • This review summarizes design, preparation and application of artificial mucins. Mucus is an essential barrier material that separates organisms from the outside world. This slippery material regulates the transport of nutrients, drugs, gases, and pathogens toward the cell surface. The surface of the cell itself is coated in a mucus-like barrier of glycoproteins and glycolipids. Mucin glycoproteins are the primary component of mucus and the epithelial glycocalyx. Aberrant mucin production is implicated in diverse disease states from cancer and inflammation to pre-term birth and infection. Biological mucins are inherently heterogenous in structure, which has challenged understanding their molecular functions as a barrier and as biochemically active proteins. Therefore, many synthetic materials have been developed as artificial mucins with precisely tunable structures. This review highlights advances in design and synthesis of artificial mucins and their application in biomedical studies of mucin chemistry, biology, and physics. [ABSTRACT FROM AUTHOR]

Carboxyl functional groups of poly(L-glutamic acid) (PGlu) were modified with a D-(+)-glucosamine (GlcN) by amidation using 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4- methylmorpholinium chloride (DMTMM) as a coupling reagent. The coupling reaction was performed in aqueous medium without protection of hydroxyl functional groups of D-(+)-glucosamine. Poly(L-glutamic acid) and GlcN functionalized polyglutamates (P(Glu-GlcN)) were thoroughly characterized by 1D and 2D NMR spectroscopy and SEC-MALS to gain detailed information on their structure, composition and molar mass characteristics. The results reveal successful functionalization with GlcN through the amide bond and also to a minor extent through ester bond formation in position 1 of GlcN. In addition, a ratio between the α- and β-form of glucosamine substituent coupled to polyglutamate repeating units as well as the content of residual dimethoxy triazinyl active ester moiety in the samples were evaluated. [ABSTRACT FROM AUTHOR]

The cellular glycocalyx is involved in diverse biological phenomena in health and disease. Yet, molecular level studies have been challenged by a lack of tools to precisely manipulate this heterogeneous structure. Engineering of the cell surface using insertion of hydrophobic-terminal materials has emerged as a simple and efficient method with great promise for glycocalyx studies. However, there is a dearth of information about how the structure of the material affects membrane insertion efficiency and resulting density, the residence time of the material, or what types of cells can be utilized. Here, we examine a panel of synthetic mucin structures terminated in highly efficient cholesterylamide membrane anchors for their ability to engineer the glycocalyx of five different cell lines. We examined surface density, residence time and half-life, cytotoxicity, and the ability be passed to daughter cells. We report that this method is robust for a variety of polymeric structures, long-lasting, and well-tolerated by a variety of cell lines., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Wardzala, Clauss and Kramer.)

Abstract: For the development of biomimetic carriers for stimuli-sensitive delivery of anticancer drugs, a novel amphiphilic glycopolypeptide conjugate containing the disulfide bond was prepared for the first time by the ring-opening polymerization of benzyl glutamate N-carboxy anhydride in the presence of (propargyl carbamate)ethyl dithio ethylamine and then click conjugation with α-azido dextran. Its structure was characterized by Fourier-transform infrared spectroscopy and nuclear magnetic resonance analyses. Owing to its amphiphilic nature, such a conjugate could self assemble into nanosize micelles in aqueous medium, as confirmed by fluorometry, transmission electron microscopy and dynamic light scattering. For the resultant micelles, it was found to encapsulate poorly water-soluble anticancer drug (methotrexate, MTX) with the loading efficiency of 45.2%. By the in vitro drug release tests, the release rate of encapsulated MTX was observed to be accelerated significantly in the presence of 10mM 1,4-dithio-DL-threitol (DTT), analogous to the intracellular redox potential. [Copyright &y& Elsevier]

In the human stomach, Helicobacter pylori, an ulcer pathogenic bacterium, colonizes the gastric mucosal layer primarily. The ability of glycopolypeptides (GPP) prepared from buttermilk to exfoliate H. pylori bound to gastric mucin was investigated. The GPP were prepared from buttermilk by digestion with trypsin, papain, pancreatin, bromelain, or pepsin. Helicobacter pylori ATCC 43504T and 43579 adhered more strongly to all of the GPP tested than to whole buttermilk, the soluble fraction of buttermilk, gastric mucin prepared from mouse stomach, or commercial pig gastric mucin. The GPP digested with trypsin, papain, or pancreatin were significantly more adherent. When the GPP concentration was 10 mg/mL, bound H. pylori ATCC 43504T, 43579, and 5 clinical isolates were exfoliated markedly from immobilized porcine gastric mucin following treatment with GPP digested with trypsin or pancreatin. This ability of GPP did not correlate with sialic acid content, indicating that sialic acid content is not important in the exfoliation of this microorganism. Such an ability may depend on the structure or number of sugar chains, or the position of sialic acid. We conclude that GPP promote the exfoliation of H. pylori bound to gastric mucin and prevent the de novo adherence of this microorganism. As such, GPP are a promising food material for preventing H. pylori infection. [ABSTRACT FROM AUTHOR]

The pH-responsive polymeric micelles (PMs) have been widely used as smart nano drug delivery systems to treat tumors. However, synchronously manipulating these PMs' self-assembly properties, drug release dynamics and tracing their pH-dependent intracellular fate remain challenges. Herein, we have first synthesized hyaluronic acid (HA) based glycopolypeptides modified by tetraphenylethylene (TPE) and a pH-sensitive doxorubicin (DOX) prodrug through Diels-Alder reaction, respectively. Then, the pH-responsive nanocomplexes (NCs) were prepared by coassembling the two obtained glycopolypeptides with different formulations. Controllable size within the range of 60-125 nm and morphologies like spherical, vesicular and oblate micelles can be easily accomplished by using this method; High drug encapsulating and loading efficiency can be easily realized and adjusted within a range of 86-97% and 7-25%, respectively; Acid sensitive drug release dynamics of these NCs are also tunable by using this way. Additionally, the programmed drug release induced by subtle pH variations can be extracellularly self-indicated by detecting the blue AIE changes of the TPE units through fluorescence resonance energy transfer (FRET) effect between DOX and TPE. More importantly, the dynamic pH-triggered DOX release can be easily traced inside the tumor cells by visualizing blue emission changes of the TPE through the FRET effect. In addition, both the size and the shape can affect the endocytic routes of the NCs; The HA coated NCs targeting the tumor cells can effectively inhibit the proliferation of the HeLa cells. This work can provide a new route to acquire the stimuli-responsive self-indicating PMs with the ability to adjust their self-assembly properties and their pH-triggered drug release dynamics, and even to simultaneously visualize the PMs' intracellular fate in a real-time., Competing Interests: Declaration of competing interest No competing interest to declare, (Copyright © 2022 Elsevier B.V. All rights reserved.)

This study aimed to characterize the emulsifying activity of biosurfactants extracted from lactic acid bacteria (LAB) originals of the Argentinian Patagonia. Nine LABs were isolated from sheep cheese and fishes. All the strains produced cell-bound biosurfactants. Four selected strains produced biosurfactants able to decrease the air/water surface tension within the range of 28.1 mN/m–19.0 mN/m and exhibited an emulsification index after 24 h storage between 82 and 98%. An evaluation of the droplet size of emulsions revealed that the use of cell-free supernatant (CFS) obtained from Lactobacillus pentosus Tw226, Lactococcus lactis ssp lactis Tw12 and Lactococcus paraplantarum LbTw7 promoted the highest reduction in the Sauter and the De Broucker diameter demonstrating that the CFSs contained biosurfactants useful to form and stabilize oil in water emulsions. Moreover, a production of 0.26 ± 0.04 g of crude biosurfactant per gram of dry Lactobacillus pentosus Tw226 biomass was obtained. This yield was the highest registered among evaluated strains. Finally, thanks to its promising features it was selected for a preliminary characterization showing a critical micelle concentration of 0.11 g/L and a glycopolypeptide structure. This study demonstrated the potential uses of this biosurfactant as emulsifying agent in food products. [ABSTRACT FROM AUTHOR]

The targeted delivery of chemotherapy drugs to tumor lesions is a major challenge for the treatment of tumors. Up until now, various polymeric nanoparticles have been explored to improve the targetability of these therapeutic drugs through passive or active targeting processes. In the design and construction of polymer nanoparticles, glycopolypeptide has shown great potential owing to its excellent targeting ability and biocompatibility. In order to enhance the antitumor effect of doxorubicin (DOX), a glycopolypeptide-based micelle (GPM) modified by α-lactose (Lac) was synthesized for targeted treatment of hepatoma. The DOX-loaded GPM (i.e., GPM/DOX) could significantly target human hepatoma (HepG2) cells and further inhibit their proliferation in vitro. Additionally, GPM/DOX exhibited a much higher drug accumulation in tumor tissue and a stronger antitumor effect in vivo than free DOX. The above results revealed that this drug delivery system provides a promising platform for the targeting therapy of hepatic cancer. [ABSTRACT FROM AUTHOR]