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TransVaccIL - Vacination per skin permeation of antigenic proteins, structured and functionally stabilized, carried by ionic liquid


The Brazilian Ministry of Health offers free vaccines against several serious diseases and private vaccination clinics offer many more, and the subcutaneous (SC) and intramuscular (IM) routes are the most used for vaccinations and are responsible for the possible effects and events at the place of application. These facts emphasize the interest of safe, effective and innovative alternatives to administration routes and antigen-releasing systems. Ionic liquids (ILs) have recently emerged as potential skin permeation promoting substances capable of improving delivery of therapeutic agents to the deeper layers of the skin. These compounds are liquid salts that can be prepared from inexpensive GRAS (Generally Recognized As Safe) materials and are extremely stable at high temperatures and pressures. While the strength of the ionic bonds renders most of the salts solid, the high size of certain molecules reduces the melting points of the salts such that they are liquid at room temperature while exhibiting high viscosity. ILs can overcome the barrier barriers of the stratum corneum and thus may be able to collaborate in topical vaccination. If ILs promote the delivery of antigenic proteins to the body through transdermal permeation, they could in many cases be as effective as subcutaneous and intramuscular vaccines, especially if they exhibit minimal cytotoxic effects on human cell lines. Of the several ILs researched in the scientific literature, choline geranate emerged as a multivalent IL because it exhibited antimicrobial activity, minimal toxicity to epithelial cells as well as to the skin and efficacy in the release of active principles by the promotion of cutaneous permeation. Thus, the use of choline geranate may potentiate increased transdermal delivery of protein molecules. The way in which ILs de-structure the horny layer is still unclear, which emphasizes the need for a deeper understanding of its mechanism of action. Considering that around 41,000 human papillomavirus (HPV) cancers occur in the United States each year, ILs may present important benefits through the alternative route of administration, since vaccines that use the IM route, in particular, cause its common adverse reactions, local manifestations of the application, such as pain, erythema, and edema. Based on these facts, this research project aims to develop a transdermal delivery system capable of protecting and stabilizing bioactive proteinic entities (using HPV4 vaccine antigens as model antigens). The development of an ionic liquid formulation capable of structurally and functionally stabilizing L1 proteins of HPV types 6,11,16,18 will include the following steps: synthesis of the ionic liquid; incorporation of the L1 proteins (HPV4 vaccine) into the synthesized ionic liquid; evaluation of permeability through in vitro permeation studies using Franz diffusion cells with pig ear skin as membrane mimicking human skin and histological evaluation throughout the permeation assays; evaluation of cytotoxicity potential by MTT assay using murine 3T3 fibroblasts, immunological viability by the cellular model RAW 264.7 and evaluation of the storage stability of the ionic liquid formulation containing the stabilized protein entities in terms of maintaining their structural and functional characteristics. (AU)

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