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Open Access Publications from the University of California

Scholarly Works (5 results)

  • Article
  • Peer Reviewed
UC Davis Previously Published Works (2024)
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.
    Cover page: A Tunable Glycosaminoglycan–Peptide Nanoparticle Platform for the Protection of Therapeutic Peptides
    • Article
    • Peer Reviewed
    UC Davis Previously Published Works (2021)
    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.
      Cover page: Glycosaminoglycans in Tissue Engineering: A Review
      • Thesis
      • Peer Reviewed
      UC Davis Electronic Theses and Dissertations (2022)

      Atopic dermatitis (AD) is a chronic, recurring, inflammatory condition of the epidermis characterized by pruritis and itching, with clearly delineated margins, that affects approximately 20% of children worldwide. The cause of AD is not understood but in recent years it has become clear that the symptoms of AD are driven by disrupted balances in cytokine and chemokine signaling, immune cell recruitment, activation, and phenotype, genetics, microbial dysregulation, and causal or symptomatic barrier dysfunction. Following an “Outside-in” model, AD is caused by disrupted barrier function of the epidermis, often due to mutations in genes coding proteins essential for proper function of the cornified envelope. This leads to ingress of exogenous antigens which then trigger inflammation driven by Th2 cells, a myriad of resident immune cells, and keratinocytes. Following an “inside-out” model of AD progression, immune dysregulation, potentially due to epigenetic mutations in cells such as CLA+ T memory cells, leads to rampant inflammation and degradation of the cornified envelope by epidermal basification and impaired barrier protein secretion by inflamed keratinocytes.One potential way to halt this inflammatory loop is via inhibition of the MAP kinase pathway, which promotes secretion inflammatory cytokines via stabilization of mRNA. Our lab has developed a family of MAP kinase inhibitor peptides (MK2i) that may prove useful in this endeavor. However, like all unmodified peptides, their effectiveness is limited by short half-life in vitro and in vivo. In this work, we introduce a novel nanoparticle platform consisting of glycosaminoglycans electrostatically coupled with MK2i and show that they enhance efficacy of MK2i in reducing inflammation in an in vitro model of keratinocyte inflammation by protecting it from enzymatic degradation. We also assess the stability of these new nanoparticles and delve into the differences between two synthesis methods. Lastly, we use sulfated hyaluronic acid at various molecular weights as a dermatan sulfate analog to explore the role sulfation and molecular weight play in particle formation and ascertain if this nanoparticle technology can be used with other peptides.

        • Article
        • Peer Reviewed
        UC Davis Previously Published Works (2023)
        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.
          Cover page: Mitigating neutrophil trafficking and cardiotoxicity with DS–IkL in a microphysiological system of a cytokine storm
          • Article
          • Peer Reviewed
          UC Davis Previously Published Works (2022)

          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.
            Cover page: Selectin-targeting glycosaminoglycan-peptide conjugate limits neutrophil-mediated cardiac reperfusion injury
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