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1.
Pharmaceutics ; 16(2)2024 Jan 25.
Article in English | MEDLINE | ID: mdl-38399234

ABSTRACT

The popularity of Glycosaminoglycans (GAGs) in drug delivery systems has grown as their innate ability to sequester and release charged molecules makes them adept in the controlled release of therapeutics. However, peptide therapeutics have been relegated to synthetic, polymeric systems, despite their high specificity and efficacy as therapeutics because they are rapidly degraded in vivo when not encapsulated. We present a GAG-based nanoparticle system for the easy encapsulation of cationic peptides, which offers control over particle diameter, peptide release behavior, and swelling behavior, as well as protection from proteolytic degradation, using a singular, organic polymer and no covalent linkages. These nanoparticles can encapsulate cargo with a particle diameter range spanning 130-220 nm and can be tuned to release cargo over a pH range of 4.5 to neutral through the modulation of the degree of sulfation and the molecular weight of the GAG. This particle system also confers better in vitro performance than the unencapsulated peptide via protection from enzymatic degradation. This method provides a facile way to protect therapeutic peptides via the inclusion of the presented binding sequence and can likely be expanded to larger, more diverse cargo as well, abrogating the complexity of previously demonstrated systems while offering broader tunability.

2.
Lab Chip ; 23(13): 3050-3061, 2023 06 28.
Article in English | MEDLINE | ID: mdl-37278194

ABSTRACT

A feature of severe COVID-19 is the onset of an acute and intense systemic inflammatory response referred to as the "cytokine storm". The cytokine storm is characterized by high serum levels of inflammatory cytokines and the subsequent transport of inflammatory cells to damaging levels in vital organs (e.g., myocarditis). Immune trafficking and its effect on underlying tissues (e.g., myocardium) are challenging to observe at a high spatial and temporal resolution in mouse models. In this study, we created a vascularized organ-on-a-chip system to mimic cytokine storm-like conditions and tested the effectiveness of a novel multivalent selectin-targeting carbohydrate conjugate (composed of DS - dermatan sulfate and IkL - a selectin-binding peptide, termed DS-IkL) in blocking infiltration of polymorphonuclear leukocytes (PMN). Our data shows that cytokine storm-like conditions induce endothelial cells to produce additional inflammatory cytokines and facilitate infiltration of PMNs into tissue. Treatment of tissues with DS-IkL (60 µM) reduced PMN accumulation in the tissue by >50%. We then created cytokine storm-like conditions in a vascularized cardiac tissue-chip and found that PMN infiltration increases the spontaneous beating rate of the cardiac tissue, and this effect is eliminated by treatment with DS-IkL (60 µM). In summary, we demonstrate the utility of an organ-on-a-chip platform to mimic COVID-19 related cytokine storm and that blocking leukocyte infiltration with DS-IkL could be a viable strategy to mitigate associated cardiac complications.


Subject(s)
COVID-19 , Neutrophils , Mice , Animals , Cardiotoxicity , Endothelial Cells , Microphysiological Systems , Cytokines
3.
Colloids Surf B Biointerfaces ; 222: 113112, 2023 Feb.
Article in English | MEDLINE | ID: mdl-36599186

ABSTRACT

Therapeutic peptides capable of reducing inflammation via inhibition of the MAP kinase 2 pathway have the potential to reduce inflammation in atopic dermatitis by suppressing secretion of inflammatory cytokines by resident keratinocytes. One of the biggest hurdles to the use of therapeutic peptides, however, is their rapid degradation by intrinsic proteases and peptidases found in serum. Here we introduce a new nanoparticle technology that enhances and extends the bioactivity of a MAP KAP kinase 2 inhibitor peptide (MK2i) via electrostatic complexation with Dermatan sulfate (DS), a glycosaminoglycan, and explore their properties under various conditions. DS-MK2i nanoparticles can be made using electrospray ionization or sonication and vortexing with no stabilizing polymers or crosslinking. Average particle diameter, polydispersity index, and zeta potential were measured over a pH range of 2.5-11.5, in increments of 0.5, in water and at physiological ionic strength. Both particle types were shown to be shelf stable, robust, and behave differently in response to pH. They are also significantly more effective at suppressing cytokine secretion in inflamed, human keratinocytes than peptide alone in the presence of serum, providing a facile method of protecting peptides for therapeutic delivery in conditions such as atopic dermatitis, and abrogating the need for serum-starvation in in vitro testing.


Subject(s)
Dermatitis, Atopic , Nanoparticles , Humans , Dermatitis, Atopic/drug therapy , Glycosaminoglycans , Peptides/chemistry , Nanoparticles/chemistry , Inflammation
4.
Cardiovasc Res ; 118(1): 267-281, 2022 01 07.
Article in English | MEDLINE | ID: mdl-33125066

ABSTRACT

AIMS: One of the hallmarks of myocardial infarction (MI) is excessive inflammation. During an inflammatory insult, damaged endothelial cells shed their glycocalyx, a carbohydrate-rich layer on the cell surface which provides a regulatory interface to immune cell adhesion. Selectin-mediated neutrophilia occurs as a result of endothelial injury and inflammation. We recently designed a novel selectin-targeting glycocalyx mimetic (termed DS-IkL) capable of binding inflamed endothelial cells. This study examines the capacity of DS-IkL to limit neutrophil binding and platelet activation on inflamed endothelial cells, as well as the cardioprotective effects of DS-IkL after acute myocardial infarction. METHODS AND RESULTS: In vitro, DS-IkL diminished neutrophil interactions with both recombinant selectin and inflamed endothelial cells, and limited platelet activation on inflamed endothelial cells. Our data demonstrated that DS-IkL localized to regions of vascular inflammation in vivo after 45 min of left anterior descending coronary artery ligation-induced MI. Further, findings from this study show DS-IkL treatment had short- and long-term cardioprotective effects after ischaemia/reperfusion of the left anterior descending coronary artery. Mice treated with DS-IkL immediately after ischaemia/reperfusion and 24 h later exhibited reduced neutrophil extravasation, macrophage accumulation, fibroblast and endothelial cell proliferation, and fibrosis compared to saline controls. CONCLUSIONS: Our findings suggest that DS-IkL has great therapeutic potential after MI by limiting reperfusion injury induced by the immune response.


Subject(s)
Anti-Inflammatory Agents/pharmacology , E-Selectin/metabolism , Endothelial Cells/drug effects , Myocardial Infarction/prevention & control , Myocardial Reperfusion Injury/prevention & control , Neutrophil Activation/drug effects , Neutrophil Infiltration/drug effects , Neutrophils/drug effects , Animals , Cell Adhesion/drug effects , Cell Proliferation/drug effects , Cells, Cultured , Disease Models, Animal , Endothelial Cells/immunology , Endothelial Cells/metabolism , Endothelial Cells/pathology , Female , Fibrosis , Humans , Male , Mice, Inbred C57BL , Myocardial Infarction/immunology , Myocardial Infarction/metabolism , Myocardial Infarction/pathology , Myocardial Reperfusion Injury/immunology , Myocardial Reperfusion Injury/metabolism , Myocardial Reperfusion Injury/pathology , Myocardium/immunology , Myocardium/metabolism , Myocardium/pathology , Neutrophils/immunology , Neutrophils/metabolism , Platelet Activation/drug effects , Signal Transduction
5.
Biomolecules ; 11(1)2020 12 29.
Article in English | MEDLINE | ID: mdl-33383795

ABSTRACT

Glycosaminoglycans are native components of the extracellular matrix that drive cell behavior and control the microenvironment surrounding cells, making them promising therapeutic targets for a myriad of diseases. Recent studies have shown that recapitulation of cell interactions with the extracellular matrix are key in tissue engineering, where the aim is to mimic and regenerate endogenous tissues. Because of this, incorporation of glycosaminoglycans to drive stem cell fate and promote cell proliferation in engineered tissues has gained increasing attention. This review summarizes the role glycosaminoglycans can play in tissue engineering and the recent advances in their use in these constructs. We also evaluate the general trend of research in this niche and provide insight into its future directions.


Subject(s)
Biocompatible Materials/metabolism , Glycosaminoglycans/metabolism , Tissue Engineering/methods , Animals , Biocompatible Materials/chemistry , Cell Communication , Cell Differentiation , Cell Proliferation , Extracellular Matrix/chemistry , Extracellular Matrix/metabolism , Glycosaminoglycans/chemistry , Humans , Stem Cells/cytology , Stem Cells/metabolism , Tissue Scaffolds/chemistry
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