Co-encapsulation of paclitaxel and C6 ceramide in tributyrin-containing nanocarriers improve co-localization in the skin and potentiate cytotoxic effects in 2D and 3D models

Autor(es)

Carvalho, Vanessa F. M. ^[1] ; Migotto, Amanda ^[1] ; Giacone, Daniela V. ^[1] ; de Lemos, Debora P. ^[1] ; Zanoni, Thalita B. ^[2] ; Maria-Engler, Silvya S. ^[2] ; Costa-Lotufo, Leticia V. ^[1] ; Lopes, Luciana B. ^[1]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Inst Biomed Sci, Sao Paulo - Brazil

^[2] Univ Sao Paulo, Sch Pharmaceut Sci, Sao Paulo - Brazil

• Tipo de documento: Artigo Científico
• Fonte: European Journal of Pharmaceutical Sciences; v. 109, p. 131-143, NOV 15 2017.
• Citações Web of Science: 9

Resumo

Considering that tumor development is generally multifactorial, therapy with a combination of agents capable of potentiating cytotoxic effects is promising. In this study, we co-encapsulated C6 ceramide (0.35%) and paclitaxel (0.50%) in micro and nanoemulsions containing tributyrin (a butyric acid pro-drug included for potentiation of cytotoxicity), and compared their ability to co-localize the drugs in viable skin layers. The nanoemulsion delivered 2- and 2.4-fold more paclitaxel into viable skin layers of porcine skin in vitro at 4 and 8 h post-application than the microemulsion, and 1.9-fold more C6 ceramide at 8 h. The drugs were co-localized mainly in the epidermis, suggesting the nanoemulsion ability for a targeted delivery. Based on this result, the nanoemulsion was selected for evaluation of the nanocarrier-mediated cytotoxicity against cells in culture (2D model) and histological changes in a 3D melanoma model. Encapsulation of the drugs individually decreased the concentration necessary to reduce melanoma cells viability to 50% (EC50) by approximately 4- (paclitaxel) and 13-fold (ceramide), demonstrating an improved nanoemulsion-mediated drug delivery. Co-encapsulation of paclitaxel and ceramide further decreased EC50 by 2.5-4.5-fold, and calculation of the combination index indicated a synergistic effect. Nanoemulsion topical administration on 3D bioengineered melanoma models for 48 h promoted marked epidermis destruction, with only few cells remaining in this layer. This result demonstrates the efficacy of the nanoemulsion, but also suggests non-selective cytotoxic effects, which highlights the importance of localizing the drugs within cutaneous layers where the lesions develop to avoid adverse effects. (AU)

• Processo FAPESP: 16/04913-9 - Avaliação de microemulsões catiônicas como sistemas capazes de aumentar a retenção cutânea e citotoxicidade de fármacos
• Beneficiário: Daniela Veronesi Giacone
• Modalidade de apoio: Bolsas no Brasil - Iniciação Científica
• Processo FAPESP: 13/16617-7 - Sistemas nanoestruturados tópicos para co-localização de agentes quimioterápicos e quimiopreventivos na pele e mama
• Beneficiário: Luciana Biagini Lopes
• Modalidade de apoio: Auxílio à Pesquisa - Jovens Pesquisadores
• Processo FAPESP: 15/23976-9 - Desenvolvimento, caracterização e avaliação de microemulsões para veiculação tópica de paclitaxel e ceramida C6
• Beneficiário: Amanda Migotto
• Modalidade de apoio: Bolsas no Brasil - Iniciação Científica
• Processo FAPESP: 14/23673-3 - Sistemas nanoestruturados tópicos para co-localização de agentes quimioterápicos e quimiopreventivos na pele e mama
• Beneficiário: Débora Pelaes de Lemos
• Modalidade de apoio: Bolsas no Brasil - Programa Capacitação - Treinamento Técnico
• Processo FAPESP: 14/24400-0 - Modelos in vitro para estudos pré-clínicos de melanoma quimioresistente
• Beneficiário: Silvya Stuchi Maria-Engler
• Modalidade de apoio: Auxílio à Pesquisa - Regular