International Journal of Nanomedicine (Mar 2016)
Novel therapeutic mechanisms determine the effectiveness of lipid-core nanocapsules on melanoma models
Abstract
Carine C Drewes,1,* Luana A Fiel,2,* Celina G Bexiga,1 Ana Carolina C Asbahr,3 Mayara K Uchiyama,4 Bruno Cogliati,5 Koiti Araki,4 Sílvia S Guterres,2,3 Adriana R Pohlmann,2,3,6 Sandra P Farsky1 1Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences, University of São Paulo, São Paulo, 2Postgraduate Program in Pharmaceutical Sciences, Federal University of Rio Grande do Sul, Porto Alegre, 3Postgraduate Program in Pharmaceutical Nanotechnology, Federal University of Rio Grande do Sul, Porto Alegre, 4Department of Fundamental Chemistry, Institute of Chemistry, 5Department of Pathology, Faculty of Veterinary Medicine, University of São Paulo, São Paulo, 6Department of Organic Chemistry, Institute of Chemistry, Federal University of Rio Grande do Sul, Porto Alegre, Brazil *These authors contributed equally to this work Abstract: Melanoma is a severe metastatic skin cancer with poor prognosis and no effective treatment. Therefore, novel therapeutic approaches using nanotechnology have been proposed to improve therapeutic effectiveness. Lipid-core nanocapsules (LNCs), prepared with poly(ε-caprolactone), capric/caprylic triglyceride, and sorbitan monostearate and stabilized by polysorbate 80, are efficient as drug delivery systems. Here, we investigated the effects of acetyleugenol-loaded LNC (AcE-LNC) on human SK-Mel-28 melanoma cells and its therapeutic efficacies on melanoma induced by B16F10 in C57B6 mice. LNC and AcE-LNC had z-average diameters and zeta potential close to 210 nm and -10.0 mV, respectively. CytoViva® microscopy images showed that LNC and AcE-LNC penetrated into SK-Mel-28 cells, and remained in the cytoplasm. AcE-LNC in vitro treatment (18–90×109 particles/mL; 1 hour) induced late apoptosis and necrosis; LNC and AcE-LNC (3–18×109 particles/mL; 48 hours) treatments reduced cell proliferation and delayed the cell cycle. Elevated levels of nitric oxide were found in supernatant of LNC and AcE-LNC, which were not dependent on nitric oxide synthase expressions. Daily intraperitoneal or oral treatment (days 3–10 after tumor injection) with LNC or AcE-LNC (1×1012 particles/day), but not with AcE (50 mg/kg/day, same dose as AcE-LNC), reduced the volume of the tumor; nevertheless, intraperitoneal treatment caused toxicity. Oral LNC treatment was more efficient than AcE-LNC treatment. Moreover, oral treatment with nonencapsulated capric/caprylic triglyceride did not inhibit tumor development, implying that nanocapsule supramolecular structure is important to the therapeutic effects. Together, data herein presented highlight the relevance of the supramolecular structure of LNCs to toxicity on SK-Mel-28 cells and to the therapeutic efficacy on melanoma development in mice, conferring novel therapeutic mechanisms to LNC further than a drug delivery system. Keywords: capric/caprylic triglycerides, mice, acetyleugenol, B16F10 cells, SK-Mel-28, nitric oxide, cell proliferation, nanotoxicology
