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Cargo-less nanoparticles program innate immune cell responses to toll-like receptor activation.
Casey, Liam M; Kakade, Sandeep; Decker, Joseph T; Rose, Justin A; Deans, Kyle; Shea, Lonnie D; Pearson, Ryan M.
Affiliation
  • Casey LM; Department of Chemical Engineering, University of Michigan, 2300 Hayward Avenue, Ann Arbor, MI, 48105, USA.
  • Kakade S; Department of Biomedical Engineering, University of Michigan, 1119 Carl A. Gerstacker Building, 2200 Bonisteel Boulevard, Ann Arbor, MI, 48109-2099, USA.
  • Decker JT; Department of Biomedical Engineering, University of Michigan, 1119 Carl A. Gerstacker Building, 2200 Bonisteel Boulevard, Ann Arbor, MI, 48109-2099, USA.
  • Rose JA; Department of Biomedical Engineering, University of Michigan, 1119 Carl A. Gerstacker Building, 2200 Bonisteel Boulevard, Ann Arbor, MI, 48109-2099, USA.
  • Deans K; Department of Biomedical Engineering, University of Michigan, 1119 Carl A. Gerstacker Building, 2200 Bonisteel Boulevard, Ann Arbor, MI, 48109-2099, USA.
  • Shea LD; Department of Chemical Engineering, University of Michigan, 2300 Hayward Avenue, Ann Arbor, MI, 48105, USA; Department of Biomedical Engineering, University of Michigan, 1119 Carl A. Gerstacker Building, 2200 Bonisteel Boulevard, Ann Arbor, MI, 48109-2099, USA. Electronic address: ldshea@umich.edu.
  • Pearson RM; Department of Biomedical Engineering, University of Michigan, 1119 Carl A. Gerstacker Building, 2200 Bonisteel Boulevard, Ann Arbor, MI, 48109-2099, USA; Department of Pharmaceutical Sciences, University of Maryland, 20 N. Pine Street, Baltimore, MD, 21201, USA. Electronic address: rpearson@rx.umary
Biomaterials ; 218: 119333, 2019 10.
Article in En | MEDLINE | ID: mdl-31301576
Developing biomaterials to control the responsiveness of innate immune cells represents a clinically relevant approach to treat diseases with an underlying inflammatory basis, such as sepsis. Sepsis can involve activation of Toll-like receptor (TLR) signaling, which activates numerous inflammatory pathways. The breadth of this inflammation has limited the efficacy of pharmacological interventions that target a single molecular pathway. Here, we developed cargo-less particles as a single-agent, multi-target platform to elicit broad anti-inflammatory action against innate immune cells challenged by multiple TLR agonists. The particles, prepared from poly(lactic-co-glycolic acid) (PLGA) and poly(lactic acid) (PLA), displayed potent molecular weight-, polymer composition-, and charge-dependent immunomodulatory properties, including downregulation of TLR-induced costimulatory molecule expression and cytokine secretion. Particles prepared using the anionic surfactant poly(ethylene-alt-maleic acid) (PEMA) significantly blunted the responses of antigen presenting cells to TLR4 (lipopolysaccharide) and TLR9 (CpG-ODN) agonists, demonstrating broad inhibitory activity to both extracellular and intracellular TLR ligands. Interestingly, particles prepared using poly(vinyl alcohol) (PVA), a neutrally-charged surfactant, only marginally inhibited inflammatory cytokine secretions. The biochemical pathways modulated by particles were investigated using TRanscriptional Activity CEll aRrays (TRACER), which implicated IRF1, STAT1, and AP-1 in the mechanism of action for PLA-PEMA particles. Using an LPS-induced endotoxemia mouse model, administration of PLA-PEMA particles prior to or following a lethal challenge resulted in significantly improved mean survival. Cargo-less particles affect multiple biological pathways involved in the development of inflammatory responses by innate immune cells and represent a potentially promising therapeutic strategy to treat severe inflammation.
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Full text: 1 Database: MEDLINE Main subject: Toll-Like Receptors / Nanoparticles / Immunity, Innate Limits: Animals Language: En Year: 2019 Type: Article

Full text: 1 Database: MEDLINE Main subject: Toll-Like Receptors / Nanoparticles / Immunity, Innate Limits: Animals Language: En Year: 2019 Type: Article