Pharmaceutical Formulations & Drug Delivery

The potenÆŸ al benefi ts of skin delivery of vaccines derive from the presence of a network of anÆŸ gen presenÆŸ ng cells (APCs) in the skin layer. TargeÆŸ ng receptors, including the DecÆŸ n-1 receptor, present on skin dendriÆŸ c cells (SDCs) should result in enhanced immunogenicity of a vaccine. We focused our aÆ© enÆŸ on on the two major agonists of the DecÆŸ n-1 receptor, β-(1-3)-glucans and mannans, and we put in place two diff erent strategies to target the SDSs. In the fi rst one a syntheÆŸ c β-(1-3)-glucan hexasaccharide, that acÆŸ vates the innate immune response by interacÆŸ on with the C-type lecÆŸ n-like DecÆŸ n-1 receptor,was chemically conjugated to the geneÆŸ cally detoxifi ed diphtheria toxin anÆŸ gen. We demonstrated that the in vitro acÆŸ vaÆŸ on of the receptor was impacted by the presentaÆŸ on ofthe glucan on the protein carrier. In vivo results in mice showed that the conjugaÆŸ on of the syntheÆŸ c β-(1-3)-glucan when delivered intradermally resulted in higher anÆŸ body ÆŸ ters in comparison to intramuscular immunizaÆŸ on. In the second strategy a Mannose-cholesterol amine conjugate was incorporated to a Lipid NanoparÆŸ cles (LNP) to increase the uptake by APCs rich in C-type lecÆŸ ns and improve the potency of Self Amplifying mRNA (SAM) encoding Infl uenza hemaggluÆŸ nin. The mannosylated LNP (MLNP) was evaluated in mice, by both intramuscular and intradermal administraÆŸ ons. SAM MLNP exhibited in vitro enhanced uptake in comparison to unglycosylated LNP from dendriÆŸ c cells, and in vivo more rapid onset of the anÆŸ body response. The increased binding anÆŸ body levels also translated into higher funcÆŸ onal hemaggluÆŸ nin inhibiÆŸ on ÆŸ ters, parÆŸ cularly following intradermal administraÆŸ on. Hence, the present work illustrates the benefi t of targeÆŸ ng vaccines to the ÆŸ ssue resident APCs and respecÆŸ ve approaches could be parÆŸ cularlyvaluable for the development of novel skin delivery systems.