The quest for new potent and safe adjuvants with which to skew and boost the immune response of vaccines against intracellular pathogens and cancer has led to the discovery of a series of small molecules that can activate Toll-like receptors (TLRs). Whereas many small molecule TLR agonists cope with a problematic safety profile, amphotericin B (AmpB), a Food and Drug Administration approved antifungal drug, has recently been discovered to possess TLR-triggering activity. However, its poor aqueous solubility and cytotoxicity at elevated concentrations currently hampers its development as a vaccine adjuvant. We present a new class of transiently thermoresponsive polymers that, in their native state, have a phase-transition temperature below room temperature but gradually transform into fully soluble polymers through acetal hydrolysis at endosomal pH values. RAFT polymerization afforded well-defined block copolymers that self-assemble into micellar nanoparticles and efficiently encapsulate AmpB. Importantly, nanoencapsulation strongly reduced the cytotoxic effect of AmpB but maintained its TLR-triggering capacity. Studies in mice showed that AmpB-loaded nanoparticles can adjuvant an RSV vaccine candidate with almost equal potency as a highly immunogenic oil-in-water benchmark adjuvant.
Bibliographical noteFunding Information:
B.L., L.L., and R.D.C. thank the IWT Flanders and Ghent University (BOF), respectively, for scholarships. B.G.D.G. acknowledges the FWO Flanders and the Flemish Liga Against Cancer for funding. L.N. thanks the FWO Flanders and the Alexander von Humboldt Foundation for a Feodor Lynen fellowship. L.V.H. is a junior assistant and B.S. a postdoctoral assistant of the Ghent University department of Biomedical Molecular Biology. We also thank Olivier Stephan for kindly providing us with DSB. S.V.H. thanks Silke Verdonck for her contributions in the experimental work during her master thesis.
© 2017 American Chemical Society.