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Nanomemulsions as delivery systems of methylene blue and metformin for the treatment of skin cancer: release, in vitro permeation/retention and cytotoxicity studies


Photodynamic therapy (PDT) is a therapeutic modality that has shown great potential for the treatment of neoplastic lesions, including skin cancer, by inducing the production of a highly cytotoxic agent (by the photoactivation of a photosensitizer (FTS)), causing cell death by apoptosis and/or necrosis. Methylene blue (MB) is a FTS that has adequate photophysical and photochemical properties for good therapy performance and it can be easily obtained on an industrial scale with good reproducibility and low cost.However, like other therapies, PDT can induce tumor cell resistance. The combined regimen of PDT with other therapeutic modalities (capable of acting through different mechanisms) is a new strategy in cancer therapies in order to overcome the resistance of tumor cells, increase the cytotoxic effect and the efficacy of the treatment, without increasing the toxicity to the patient. MET is a hypoglycemic that has exhibited antiproliferative action for various types of neoplasms, including skin cancer. Furthermore, it is able to act synergistically with various drugs, including with FTSs in PDT, in combating tumor cells.Therefore, the combined regimen of PDT (mediated by MB) and MET is an attractive proposal for the treatment of non-melanoma skin cancer, aiming to minimize the resistance of tumor cells as well as optimize the therapeutic response.The topical application of MB and MET in the treatment of cutaneous neoplastic lesions is a strategy to provide the therapeutic effect to a specific site and to reduce the systemic toxicity. However, for an adequate therapeutic response, the stratum corneum, the outermost layer of the skin, which prevents the drugs (AM and MET) from reaching deeper layers and at the appropriate concentration, must be overcome. Thus, the development of a system that optimizes the penetration of AM and MET, as well as minimizes systemic exposure, contributes to a more effective therapeutic response with a low rate of adverse effects.Nanoemulsions have demonstrated potential for this purpose since their constituents may interact with stratum corneum lipids increasing membrane permeability and availability of drug at the target site. In addition, the composition of these systems may modulate drug release for topical or transdermal effects and the structural organization of these systems may impose restriction on drug release, acting as true systems for the prolonged release of drugs.In view of the above, the present project proposes the obtaining of nanomemulsion based on monolein, for the cutaneous delivery of MB and MET, as well as the characterization of the systems obtained regarding to the physicochemical properties (particle size, zeta potential, diffraction X-ray at low angle, viscosity and morphology by cryo-TEM), the in vitro release profile and the in vitro cutaneous permeation/retention profile of MB and MET. In order to complement the pharmacotechnical development, cytotoxicity studies in cell culture will be carried out. (AU)

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Scientific publications
(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)
DONADON, LARISSA GABRIELLA FUSCO; SALATA, GIOVANNA CASSONE; GONCALVES, THALITA PEDRALINO; MATOS, LISA DE CARVALHO; EVANGELISTA, MARIA CLARA PAIVA; DA SILVA, NICOLE SAMPAIO; MARTINS, TEREZA SILVA; MACHADO-NETO, JOAO AGOSTINHO; LOPES, LUCIANA BIAGINI; GARCIA, MARIA TERESA JUNQUEIRA. Monoolein-based nanodispersions for cutaneous co-delivery of methylene blue and metformin: Thermal and structural characterization and effects on the cutaneous barrier, skin penetration and cytotoxicity. International Journal of Pharmaceutics, v. 633, p. 18-pg., . (17/18239-0, 18/13877-1, 17/17844-8, 19/08582-5, 19/26048-6)
MATOS, LISA DE CARVALHO; CALIXTO, LEANDRO AUGUSTO; JUNQUEIRA GARCIA, MARIA TERESA. Developing an analytical method by HPLC for simultaneous quantification of methylene blue and metformin applied to in vitro skin permeation and retention studies. BIOMEDICAL CHROMATOGRAPHY, v. 35, n. 8, . (17/18239-0)

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