Abstract
BackgroundTranscutaneous immunization (TCI) is a novel vaccination strategy, which is expected to have therapeutic applications. However, to develop effective TCI systems, a simple, non-invasive and safe transdermal formulation is required. This study developed a novel TCI system utilizing the co-administration of a liposoluble absorption enhancer, propylene glycol monocaprylate (PGMC) and hydrosoluble protein antigen without pretreatment of any typical adjuvants and disruption of the skin. Novel transdermal formulations were also prepared with sodium salicylate (NaSal) as a hydrotropic agent to improve the solubility of poorly water-soluble substances.Methodology/Principal FindingsThe TCI system, which used a transdermal formulation containing hen lysozyme (HEL) and PGMC, solubilized with NaSal, resulted in a substantial HEL-specific antibody response in an HEL dose-dependent manner even in the absence of potent adjuvants, such as cholera toxin (CT). We also investigated whether NaSal activates antigen-presenting cells in vitro to clarify the mechanisms of antibody production by the hydrotropic formulation. NaSal enhanced the expression of MHC class II molecules and increased the production of IL-12 and TNF-α in dendritic cells, which were stimulated by lipopolysaccharide in vitro, indicating that NaSal had an effective adjuvant-like property. Moreover, the use of NaSal in the TCI system did not induce an HEL-specific, IgE-dependent anaphylactic reaction.Conclusion/SignificanceOur TCI system using a hydrotropic formulation effectively and safely induced the intended immune response, and this system thus represents a new advantageous method that will result in improved TCI strategies.
Highlights
The skin is a potential site for immunotherapy, because it has important immunological functions
Co-administration of hen lysozyme (HEL) and propylene glycol monocaprylate (PGMC) solubilized in the presence of NaSal as a transdermal hydrotropic formulation resulted in substantial HEL-specific antibody production, even in the absence of a potent adjuvant, the higher anti-HEL antibody production was observed in the coadministration of HEL, PGMC, and NaSal till six weeks passed than that of HEL and cholera toxin (CT) with significant differences, and delayed response was observed in the administration of HEL and CT at eight weeks (Fig. 1A)
This study demonstrated that transdermal co-administration of HEL and PGMC solubilized in the presence of NaSal resulted in a substantial HEL-specific antibody response, similar to immunization using CT as adjuvants
Summary
The skin is a potential site for immunotherapy, because it has important immunological functions. Successful immunoadjuvants for vaccines include mineral salts, immunostimulatory cytokines, liposomes, CpG oligodeoxynucleotides, microbial products, and bacterial toxins (e.g. cholera toxin (CT) and Escherichia coli heat-labile toxin) [1,4,5,6,7,8,9,10] These immunoadjuvants are immunologically effective; most are too toxic for clinical use [6,7,8]. Fatty acids, alcohols, propylene glycol, amines, and amides all enhance chemical absorption through the skin and have been used for transdermal therapeutic systems [18,19,20]. This study developed a novel TCI system utilizing the co-administration of a liposoluble absorption enhancer, propylene glycol monocaprylate (PGMC) and hydrosoluble protein antigen without pretreatment of any typical adjuvants and disruption of the skin. Novel transdermal formulations were prepared with sodium salicylate (NaSal) as a hydrotropic agent to improve the solubility of poorly water-soluble substances
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