Potent Lymphatic Translocation and Spatial Control Over Innate Immune Activation by Polymer-Lipid Amphiphile Conjugates of Small-Molecule TLR7/8 Agonists

Angew Chem Int Ed Engl. 2019 Oct 21;58(43):15390-15395. doi: 10.1002/anie.201905687. Epub 2019 Sep 12.

Abstract

Uncontrolled systemic inflammatory immune triggering has hampered the clinical translation of several classes of small-molecule immunomodulators, such as imidazoquinoline TLR7/8 agonists for vaccine design and cancer immunotherapy. By taking advantage of the inherent serum-protein-binding property of lipid motifs and their tendency to accumulate in lymphoid tissue, we designed amphiphilic lipid-polymer conjugates that suppress systemic inflammation but provoke potent lymph-node immune activation. This work provides a rational basis for the design of lipid-polymer amphiphiles for optimized lymphoid targeting.

Keywords: immunomodulation; innate immunity; lipid amphiphiles; lymph nodes; polymers.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cholesterol / chemistry
  • Imidazoles / chemistry
  • Immunity, Innate* / drug effects
  • Immunologic Factors / chemistry
  • Immunologic Factors / metabolism
  • Immunologic Factors / pharmacology
  • Lipids / chemistry
  • Lymph Nodes / drug effects
  • Lymph Nodes / immunology
  • Macrophages / cytology
  • Macrophages / drug effects
  • Macrophages / metabolism
  • Mice
  • NF-kappa B / metabolism
  • Polymers / chemistry
  • Quinolines / chemistry
  • Quinolines / pharmacology
  • RAW 264.7 Cells
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology
  • Toll-Like Receptor 7 / agonists*
  • Toll-Like Receptor 7 / metabolism
  • Toll-Like Receptor 8 / agonists*
  • Toll-Like Receptor 8 / metabolism

Substances

  • Imidazoles
  • Immunologic Factors
  • Lipids
  • NF-kappa B
  • Polymers
  • Quinolines
  • Small Molecule Libraries
  • Toll-Like Receptor 7
  • Toll-Like Receptor 8
  • Cholesterol