LLY507 br celecoxib cytotoxicity Compared to potent

celecoxib cytotoxicity. Compared to potent cytotoxic drugs like pacli-taxel and doxorubicin, the obtained celecoxib IC50 was high, and jus-tifies its intended use to alter other pathways involved in cancer de-velopment (Carvalho et al., 2017b; Elmets et al., 2010; Fischer et al., 1999). Celecoxib incorporation in ME-60 reduced its IC50, an effect generally attributed to a more efficient drug delivery into LLY507 and/or increased solubility of lipophilic drugs in the aqueous culture medium (Migotto et al., 2018; Pepe et al., 2016; Stover and Kester, 2003). However, the fact that ME-60 droplet size increased when it was diluted in the cell culture medium, suggests some sort of formulation destabi-lization, and that (i) the increased cytotoxicity might result from the combined effects of the drug and formulation components and not necessarily from the intact microemulsion-mediated delivery, and (ii) presence of formulation components in the mammary tissue might aid drug cytotoxicity. We do not expect ME-60 to cross the skin intact, but because of the ability to puncture the skin, microneedle application might improve the amount of microemulsion components reaching the mammary tissue, and thus, aid drug cytotoxic effects against cancer cells. Future studies will focus on assessing celecoxib effect on COX-2 in vivo.
6. Conclusions
Our results demonstrate that microemulsion optimization was es-sential to combine enhancement of celecoxib penetration and for-mulation safety, and support the combination of ME-60 with micro-needles to further improve celecoxib delivery. With this study, we hope to contribute to the development of an effective, well accepted and much needed local strategy for chemoprevention of breast cancer.
Acknowledgements
This study was supported by São Paulo Research Foundation (FAPESP, grant# 2013/16617-7) and National Counsel of Technological and Scientific Development (CNPq, grant# 443549/ 2014-1). Fellowships from PIBIT/CNPq (to G. Mojeiko) and FAPESP (grant# 2017/23213-0 to G.C. Salata) are greatly appreciated. The authors would like to thank Dr. Leticia Costa-Lotufo (Institute of Biomedical Sciences, University of Sao Paulo) for use of the cell culture facility.
Appendix A. Supplementary data
References
Alber, C., Buraczewska-Norin, I., Kocherbitov, V., Saleem, S., Loden, M., Engblom, J., 2014. Effects of water activity and low molecular weight humectants on skin per-meability and hydration dynamics - a double-blind, randomized and controlled study. Int. J. Cosmet. Sci. 36, 412–418.
Bragagni, M., Mennini, N., Maestrelli, F., Cirri, M., Mura, P., 2012. Comparative study of liposomes, transfersomes and ethosomes as carriers for improving topical delivery of celecoxib. Drug Deliv. 19, 354–361.
Djekic, L., Martinovic, M., Stepanovic-Petrovic, R., Tomic, M., Micov, A., Primorac, M., 2015. Design of Block Copolymer Costabilized Nonionic Microemulsions and Their In Vitro and In Vivo Assessment as Carriers for Sustained Regional Delivery of Ibuprofen via Topical Administration. J. Pharm. Sci. 104, 2501–2512.
Elmahjoubi, E., Frum, Y., Eccleston, G.M., Wilkinson, S.C., Meidan, V.M., 2009. Transepidermal water loss for probing full-thickness skin barrier function: correlation with tritiated water flux, sensitivity to punctures and diverse surfactant exposures. Toxicol. In Vitro 23, 1429–1435.
Elnaggar, Y.S., Talaat, S.M., Bahey-El-Din, M., Abdallah, O.Y., 2016. Novel lecithin-in-tegrated liquid crystalline nanogels for enhanced cutaneous targeting of terconazole: development, in vitro and in vivo studies. Int. J. Nanomed. 11, 5531–5547.
Fischer, S.M., Lo, H.H., Gordon, G.B., Seibert, K., Kelloff, G., Lubet, R.A., Conti, C.J., 1999. Chemopreventive activity of celecoxib, a specific cyclooxygenase-2 inhibitor, and indomethacin against ultraviolet light-induced skin carcinogenesis. Mol. Carcinog. 25, 231–240.
Garti, N., Avrahami, M., Aserin, A., 2006. Improved solubilization of Celecoxib in U-type nonionic microemulsions and their structural transitions with progressive aqueous dilution. J. Colloid Interface Sci. 299, 352–365. Graf, A., Ablinger, E., Peters, S., Zimmer, A., Hook, S., Rades, T., 2008. Microemulsions containing lecithin and sugar-based surfactants: nanoparticle templates for delivery of proteins and peptides. Int. J. Pharm. 350, 351–360.
Jacques-Jamin, C., Jeanjean-Miquel, C., Domergue, A., Bessou-Touya, S., Duplan, H., 2017. Standardization of an in vitro Model for Evaluating the Bioavailability of Topically Applied Compounds on Damaged Skin: Application to Sunscreen Analysis. Skin Pharmacol. Physiol. 30, 55–65.