Noninvasive Transdermal Vaccine Platform Using Deep Eutectic Solvents for Cancer Immunotherapy

Abstract Cancer immunotherapy has attracted considerable attention since the early 2010s as an alternative to conventional cancer treatments such as surgery, chemotherapy, and radiotherapy. Among these approaches, cancer vaccines exert preventive and therapeutic effects by eliciting immune responses against tumor antigens. However, most cancer vaccines still rely on injection-based administration, which is associated with pain, the risk of secondary infection, and an increased burden on healthcare professionals. To address these limitations, we focused on noninvasive and convenient transdermal administration of cancer vaccines. Nevertheless, the transdermal delivery of hydrophilic cancer antigen peptides is considered challenging because the stratum corneum, the outermost layer of the skin, acts as a strong barrier against hydrophilic molecules and molecules with molecular weights greater than 500. To overcome this limitation, we developed a deep eutectic solvent (DES)-based formulation for transdermal cancer vaccination. In the present study, an amphiphilic DES composed of choline and oleic acid was prepared. Using this DES, a model cancer antigen peptide (SIINFEKL) was solubilized in an oil-based vehicle, yielding a transdermal formulation. Ex vivo studies demonstrated that the DES-based formulation exhibited greater skin permeation than a phosphate-buffered saline solution and a conventional ionic liquid-based formulation. Optimization with ethanol as a cosolvent yielded an advanced formulation that exhibited even higher skin permeation and showed significant tumor growth suppression in vivo. In addition, transepidermal water loss measurements after administration indicated that the advanced formulation caused little to no skin irritation. DES-based transdermal delivery systems may provide an effective strategy for overcoming the limitations of conventional injectable formulations. To our knowledge, this is the first report describing DES-based vaccine formulation with evaluation of its immunological efficacy.