Journal
EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES
Volume 109, Issue -, Pages 131-143Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.ejps.2017.07.023
Keywords
Nanoemulsion; Paclitaxel; C6 ceramide; Skin targeting; Co-localization; Bioengineered melanoma models
Categories
Funding
- Sao Paulo Research Foundation [2013/16617-7, 2014/24400-0]
- National Council of Technological and Scientific Development [443549/2014-1, 458548/2013-8]
- CNPQ
- CAPES
- FAPESP [2014/23673-3, 2015/23976-9, 2016/04913-9]
- Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) [16/04913-9] Funding Source: FAPESP
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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.
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