Hyaluronic acid nanoemulsions improve piplartine cytotoxicity in 2D and 3D breast cancer models and reduce tumor development after intraductal administration.

Nanoemulsions modified with chitosan (NE-Q) or hyaluronic acid (NE-HA), developed for intraductal administration of piplartine (piperlongumine) and local breast cancer treatment, were evaluated for cytotoxic effects in vitro in 2D and 3D breast cancer models and in vivo in a chemically induced carcinogenesis model. Droplet size was lower than 100 nm, and zeta potential varied from +17.9 to -25.5 mV for NE-Q and NE-HA, respectively. Piplartine nanoencapsulation reduced its IC up to 3.6-fold in T-47D and MCF-7 monolayers without differences between NE-Q and NE-HA, and up to 6.6-fold in cancer spheroids. Cytotoxicity improvement may result from a more efficient NE-mediated delivery, as suggested by stronger fluorescent staining of cells and spheroids. In 1-methyl-1-nitrosourea -induced breast cancer models, intraductal administration of piplartine-loaded NE-HA inhibited breast tumor development and histological alterations. These results support the potential applicability of piplartine-loaded NE-HA for intraductal treatment of breast cancer.