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TransAppIL - transdermal delivery of structurally and functionally stabilized protein entities applying ionic liquids

Grant number: 16/12234-4
Support type:Regular Research Grants
Duration: February 01, 2017 - January 31, 2019
Field of knowledge:Health Sciences - Pharmacy
Principal Investigator:Marta Maria Duarte Carvalho Vila
Grantee:Marta Maria Duarte Carvalho Vila
Home Institution: Pró-Reitoria Acadêmica. Universidade de Sorocaba (UNISO). Sorocaba , SP, Brazil
Assoc. researchers:Angela Faustino Jozala ; FERNANDO DE SÁ DEL FIOL ; José Martins de Oliveira Junior ; Matthieu Tubino ; Renata de Lima ; Vitor Manuel Cardoso Figueiredo Balcão


Hidden beneath a protective biofilm, pathogenic bacteria thrive forming authentic microbial cities and may unleash all kinds of mischief in skin infections. Bacterial biofilms are sheltered beneath the outer layer of skin, the stratum corneum, which serves as a natural barrier to most therapeutic agents. With such a double-layered protection, harmful bacteria can become especially dangerous, mainly through enhanced antibiotic resistance, which may increase 50- to 1,000-fold. Ionic liquids (ILs) are quirky chemical compounds that are able to defeat the tricky defenses of both bacteria and skin and help treat chronic wounds and wound degradation, which often result from bacterial biofilms. This clearly adds excellent prospects to ILs for aiding in the delivery of pharmaceutical compounds to the pathogen infection site through biofilm disruption. ILs are made of salts, positively and negatively charged ions held together by their charge, with low melting points so they are liquid at room temperature, exhibiting high viscosity. Of the several ILs screened in the specialty literature, choline-geranate and choline-oleate emerged as multifunctional ILs since they have been reported to exhibit excellent antimicrobial activities, minimal toxicity to epithelial cells as well as skin, and effectively enhance permeation for drug delivery to the deeper tissue layers of the skin without inducing its irritation. Skin afflictions such as acne, eczema and diabetic ulcers can get infected and develop an armored layer of bacterial cells (i.e. a biofilm) that is quite difficult to defeat. While ILs appear to disrupt the polysaccharide-based shell excreted by (pathogenic) bacteria that characterize biofilms, at the skin it is likely that the IL molecules slip in between the fatty compounds that make up skin cells, creating tiny openings through which drugs can permeate. Taking into consideration that more than three quarters of infections in human beings are associated with bacterial biofilms, linked to the fact that over 65% of hospital-acquired infections are caused by biofilms, ILs may have massive therapeutic benefits. This research project proposal aims at developing a transdermic biomimetic system with the goal of protecting and stabilizing (both structurally and functionally) bioactive (antimicrobial, antioxidant, wound healing, anti-wrinkle and skin elasticity enhancing) protein entities, while enhancing their permeation into the deeper layers of the skin, taking advantage of the use of selected ILs. The development, on one hand, of a suitable IL formulation, highly viscous, able to structurally and functionally stabilize sericin and strictly lytic bacteriophage particles and, on the other, of a hybrid biohydrogel impregnated with the IL formulation, will be followed by (i) in vitro skin permeation studies using Franz diffusion cells and porcine ear skin as membrane, simulating human skin; (ii) evaluation of the potential for citotoxicity via the MTT assay using 3T3 murine fibroblasts; (iii) evaluation of the antiinflammatory potential via determination of nitric oxide in a culture of murine macrophages (RAW 264.7) stimulated with bacterial lipopolyssacharide (LPS); (iv) evaluation of the genotoxicity potential via the Comet" assay; (v) evaluation of the antioxidant potential via the DPPH assay; and (vi) evaluation of the storage stability. (AU)

Scientific publications (8)
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
JORGE, LUDMILLA R.; HARADA, LILIAM K.; SILVA, ERICA C.; CAMPOS, WELIDA F.; MORELLI, FERNANDA C.; SHIMAMOTO, GUSTAVO; PEREIRA, JORGE F. B.; OLIVEIRA JR, JOSE M.; TUBINO, MATTHIEU; VILA, MARTA M. D. C.; BALCAO, VICTOR M. Non-invasive Transdermal Delivery of Human Insulin Using Ionic Liquids: In vitro Studies. FRONTIERS IN PHARMACOLOGY, v. 11, APR 23 2020. Web of Science Citations: 0.
BALCAO, VICTOR M.; HARADA, LILIAM K.; JORGE, LUDMILLA R.; OLIVEIRA JR, JOSE M.; TUBINO, MATTHIEU; VILA, MARTA M. D. C. Structural and Functional Stabilization of Sericin from Bombyx mori Cocoons in a Biopolysaccharide Film: Bioorigami for Skin Regeneration. Journal of the Brazilian Chemical Society, v. 31, n. 4, p. 833-848, APR 2020. Web of Science Citations: 0.
LIMA, RENATA; DEL FIOL, FERNANDO SA; BALCAO, VICTOR M. Prospects for the Use of New Technologies to Combat Multidrug-Resistant Bacteria. FRONTIERS IN PHARMACOLOGY, v. 10, JUN 21 2019. Web of Science Citations: 2.
FAVARO, LAURA I. L.; BALCAO, VICTOR M.; ROCHA, LILIAM K. H.; SILVA, ERICA C.; OLIVEIRA JR, JOSE M.; VILA, MARTA M. D. C.; TUBINO, MATTHIEU. Physicochemical Characterization of a Crude Anthocyanin Extract from the Fruits of Jussara (Euterpe edulis Martius): Potential for Food and Pharmaceutical Applications. Journal of the Brazilian Chemical Society, v. 29, n. 10, p. 2072-2088, OCT 2018. Web of Science Citations: 6.
HARADA, LILIAM K.; PEREIRA, JORGE F. B.; CAMPOS, WELIDA F.; SILVA, ERICA C.; MOUTINHO, CARLA G.; VILA, MARTA M. D. C.; OLIVEIRA, JR., JOSE M.; TEIXEIRA, JOSE A.; BALCAO, VICTOR M.; TUBINO, MATTHIEU. Insights into Protein-Ionic Liquid Interactions Aiming at Macromolecule Delivery Systems. Journal of the Brazilian Chemical Society, v. 29, n. 10, p. 1983-1998, OCT 2018. Web of Science Citations: 4.
RIOS, ALESSANDRA C.; VILA, MARTA M. D. C.; LIMA, RENATA; DEL FIOL, FERNANDO S.; TUBINO, MATTHIEU; TEIXEIRA, JOSE A.; BALCAO, VICTOR M. Structural and functional stabilization of bacteriophage particles within the aqueous core of a W/O/W multiple emulsion: A potential biotherapeutic system for the inhalational treatment of bacterial pneumonia. Process Biochemistry, v. 64, p. 177-192, JAN 2018. Web of Science Citations: 4.
HARADA, LILIAM K.; SILVA, ERICA C.; CAMPOS, WELIDA F.; DEL FIOL, FERNANDO S.; VILA, MARTA; DABROWSKA, KRYSTYNA; KRYLOV, VICTOR N.; BALCAO, VICTOR M. Biotechnological applications of bacteriophages: State of the art. MICROBIOLOGICAL RESEARCH, v. 212, p. 38-58, 2018. Web of Science Citations: 13.
ROCHA, LILIAM K. H.; FAVARO, LAURA I. L.; RIOS, ALESSANDRA C.; SILVA, ERICA C.; SILVA, WELIDA F.; STIGLIANI, TATIANE P.; GUNGER, MARIANA; LIMA, RENATA; OLIVEIRA, JR., JOSE M.; ARANHA, NORBERTO; TUBINO, MATTHIEU; VILA, MARTA M. D. C.; BALCAO, VICTOR M. Sericin from Bombyx mori cocoons. Part I: Extraction and physicochemical-biological characterization for biopharmaceutical applications. Process Biochemistry, v. 61, p. 163-177, OCT 2017. Web of Science Citations: 8.

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