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


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)

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Scientific publications (15)
(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)
CAMPOS, WELIDA F.; SILVA, ERICA C.; OLIVEIRA, THAIS J.; OLIVEIRA, JR., JOSE M.; TUBINO, MATTHIEU; PEREIRA, CARLA; VILA, MARTA M. D. C.; BALCAO, VICTOR M.. Transdermal permeation of bacteriophage particles by choline oleate: potential for treatment of soft-tissue infections. FUTURE MICROBIOLOGY, v. 15, n. 10, p. 881-896, . (16/08884-3, 18/05522-9, 16/12234-4)
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; et al. Sericin from Bombyx mori cocoons. Part I: Extraction and physicochemical-biological characterization for biopharmaceutical applications. Process Biochemistry, v. 61, p. 163-177, . (16/16641-3, 16/08884-3, 16/12234-4)
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, . (17/13328-5, 18/05522-9, 16/08884-3, 16/12234-4)
LILIAN VIEIRA VAZ; VICTOR MANUEL BALCÃO; JOSÉ MARTINS OLIVEIRA JR; MATTHIEU TUBINO; ANGELA JOZALA; VALQUÍRIA MIWA HANAI YOSHIDA; MARTA MARIA DUARTE CARVALHO VILA. Development and Characterization of a Hydrogel Containing Silver Sulfadiazine for Antimicrobial Topical Applications. Part II: Stability, Cytotoxicity and Silver Release Patterns. Brazilian Journal of Pharmaceutical Sciences, v. 58, . (16/08884-3, 16/12234-4, 18/05522-9)
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, . (13/03181-6, 16/08884-3, 16/12234-4)
HARADA, LILIAM K.; JUNIOR, WALDEMAR BONVENTI; SILVA, ERICA C.; OLIVEIRA, THAIS J.; MORELI, FERNANDA C.; JUNIOR, JOSE M. OLIVEIRA; TUBINO, MATTHIEU; VILA, MARTA M. D. C.; BALCAO, VICTOR M.. Bacteriophage-Based Biosensing of Pseudomonas aeruginosa: An Integrated Approach for the Putative Real-Time Detection of Multi-Drug-Resistant Strains. BIOSENSORS-BASEL, v. 11, n. 4, . (16/08884-3, 16/12234-4, 18/05522-9)
SILVA, ERICA C.; OLIVEIRA, THAIS J.; MORELI, FERNANDA C.; HARADA, LILIAM K.; VILA, MARTA M. D. C.; BALCAO, VICTOR M.. Newly isolated lytic bacteriophages for Staphylococcus intermedius, structurally and functionally stabilized in a hydroxyethylcellulose gel containing choline geranate: Potential for transdermal permeation in veterinary phage therapy. Research in Veterinary Science, v. 135, p. 42-58, . (18/05522-9, 16/08884-3, 16/12234-4)
HERNANDES, AUDREY N.; BOSCARIOL, RODRIGO; BALCAO, VICTOR M.; VILA, MARTA M. D. C.. Transdermal Permeation of Caffeine Aided by Ionic Liquids: Potential for Enhanced Treatment of Cellulitis. AAPS PHARMSCITECH, v. 22, n. 3, . (18/05522-9, 16/12234-4, 16/08884-3)
BOSCARIOL, RODRIGO; CAETANO, ERIKA A.; SILVA, ERICA C.; OLIVEIRA, THAIS J.; ROSA-CASTRO, RAQUEL M.; VILA, MARTA M. D. C.; BALCAO, VICTOR M.. Performance of Choline Geranate Deep Eutectic Solvent as Transdermal Permeation Enhancer: An In Vitro Skin Histological Study. PHARMACEUTICS, v. 13, n. 4, . (16/12234-4, 16/08884-3, 18/05522-9)
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.; et al. Non-invasive Transdermal Delivery of Human Insulin Using Ionic Liquids: In vitro Studies. FRONTIERS IN PHARMACOLOGY, v. 11, . (16/08884-3, 18/05522-9, 16/12234-4)
ROSA MITELMAO, FABIANA CRISTINA; BERGAMASCHI, CRISTIANE DE CASSIA; GERENUTTI, MARLI; HACHEL, KARIN; SILVA, MARCUS TOLENTINO; BALCAO, VICTOR M.; DUARTE CARVALHO VILA, MARTA MARIA. The effect of probiotics on functional constipation in adults Double-blind, randomized, placebo-controlled study. MEDICINE, v. 100, n. 10, . (18/05522-9, 16/08884-3, 16/12234-4)
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, . (16/16641-3, 18/05522-9, 16/12234-4, 16/08884-3)
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, . (16/08884-3, 16/16641-3, 16/12234-4)
HARADA, LILIAM K.; SILVA, ERICA C.; ROSSI, FERNANDO P. N.; CIEZA, BASILIO; OLIVEIRA, THAIS J.; PEREIRA, CARLA; TOMAZETTO, GEIZECLER; SILVA, BIANCA B.; SQUINA, FABIO M.; VILA, MARTA M. D. C.; et al. Characterization and in vitro testing of newly isolated lytic bacteriophages for the biocontrol of Pseudomonas aeruginosa. FUTURE MICROBIOLOGY, v. 17, n. 2, p. 111-141, . (18/05522-9, 16/12234-4, 16/08884-3)

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