Abstract
Considering that breast cancer usually begins in the lining of the ducts, local drug administration into the ducts could target cancers and pre-tumor lesions locally while reducing systemic adverse effects. In this study, a cationic bioadhesive nanoemulsion was developed for intraductal administration of C6 ceramide, a sphingolipid that mediates apoptotic and non-apoptotic cell death. Bioadhesive properties were obtained by surface modification with chitosan. The optimized nanoemulsion displayed size of 46.3 nm and positive charge, properties that were not affected by ceramide encapsulation (0.4%, w/w). C6 ceramide concentration necessary to reduce MCF-7 cells viability to 50% (EC50) decreased by 4.5-fold with its nanoencapsulation compared to its solution; a further decrease (2.6-fold) was observed when tributyrin (a pro-drug of butyric acid) was part of the oil phase of the nanocarrier, a phenomenon attributed to synergism. The unloaded nanocarrier was considered safe, as indicated by a score <0.1 in HET-CAM models, by the high survival rates of Galleria mellonella larvae exposed to concentrations ≤500 mg/mL, and absence of histological changes when intraductally administered in rats. Intraductal administration of the nanoemulsion prolonged drug localization for more than 120 h in the mammary tissue compared to its solution. These results support the advantage of the optimized nanoemulsion to enable mammary tissue localization of C6 ceramide.
Highlights
Breast cancer is one of the most prevalent types of cancer worldwide
As depicted in Figure 1(B,C), nanocarriers obtained with tributyrin at 8.5% without chitosan displayed nanometric size (39.3 ± 0.8 nm) and negative zeta potential (À2.9 ± 3.5 mV)
Nanocarriers obtained without tributyrin in the oil phase displayed nanometric size (54.0 ± 3.2 nm) and a positive zeta potential (þ7.4 ± 1.8 mV); these nanocarriers were employed in cytotoxicity experiments as controls
Summary
Breast cancer is one of the most prevalent types of cancer worldwide. It is estimated that approximately 12% of the women will be diagnosed with this disease in their lifetime (Ward et al, 2015; Groen et al, 2017). Due to the risk of progression, the current standard of care for all grades of DCIS is surgical excision (breast-conserving or mastectomy) followed by radiation therapy and oral tamoxifen for estrogen-positive tumors (Groen et al, 2017) When it comes to low-grade DCIS, this standard of care has been questioned by several groups, as recent studies have suggested that it does not seem to increase the breast cancer-specific survival for patients with low-grade DCIS at the time of diagnosis, and the rise in DCIS diagnoses (and treatment) has not been accompanied by a corresponding reduction in invasive cancer incidence (Narod et al, 2015; Sagara et al, 2015). Considering that development of the lesions start in the mammary ducts, intraductal drug administration emerges as a promising route for local treatment
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