Lipid Nature and Alkyl Length Influence Lymph Node Accumulation of Lipid-Polyethylene Glycol Amphiphiles

Immunomodulatory drugs are of great relevance in the context of vaccine delivery and cancer immunotherapy. Due to the ubiquitous presence of immune cells throughout the body, gaining control over the biodistribution and activity of such drugs is crucial to limit off-target inflammatory responses. Here, the authors report on lipid-PEG (polyethylene glycol) amphiphiles as well-defined amphiphilic carries for lymph node targeted delivery. Comparing cholesterol and dialkyl lipids with different alkyl chain length, the authors found that both the nature of the lipid, as well as, the alkyl chain length have a dramatic influence on cellular uptake and lymph node translocation. Whereas shorter dioctyl-PEG amphiphiles show overall poor performance, larger dioctadecyl-PEG amphiphiles are prone to solubility issues. Didodecyl-PEG amphiphiles with intermediate alkyl chain length are on par with cholesteryl-PEG amphiphiles in in vitro and in vivo cellular uptake and lymphoid tissue targeting. Immunization with a cholesteryl-PEG-imidazoquinoline (TLR7/8 agonist) amphiphile-adjuvanted model antigen shows induction of immune responses that are qualitatively different from Montanide-adjuvanted antigen, characterized by effector CD8(+) T cells with immediate cytotoxic potential and robust IgG2 antibody responses. These findings provide a rational base for further adjuvant design based on the type of immunity needed for a specific vaccination or therapeutic setting.

Automated summary

Immunomodulatory drugs play an important role in vaccine delivery and cancer immunotherapy. This study investigates lipid-PEG amphiphiles as carriers for lymph node targeted delivery, highlighting the significant impact of alkyl chain length on cellular uptake and lymph node translocation. Amphiphiles with intermediate alkyl chain length show promising results in cellular uptake and lymphoid tissue targeting.