• NLC production and composition were optimized based on physicochemical characteristics. • Fenretinide and POH were successfully co-encapsulated into NLCs • NLCs promoted sustained drug release and formed a local depot in the mammary tissue. • Association with perillyl alcohol enhanced fenretinide’s cellular effects. Strategies available for breast cancer chemoprevention are of limited use, partially due to adverse effects. Motivated by this clinical demand, we developed nanostructured lipid carriers (NLCs) as a subcutaneous delivery system for local fenretinide and perillyl alcohol (POH) co-delivery in the mammary tissue. NLC composition (type and content of surfactant) and production method were optimized based on the evaluation of physicochemical characteristics, and the HET-CAM model was used to assess irritation potential. The effects of NLC on cell viability, migration and ROS levels were evaluated in vitro using breast cancer cells. Lastly, we investigated the NLC in vivo localization and histological changes. Increasing polysorbate content from 1.5% to 3% reduced particle size (1.4–1.6-fold). While extended stirring (2 min) or sonication times (20 min) did not affect size, the latter promoted an increase in viscosity. The selected NLC was 281.4 ± 17.5 nm (−20.9 ± 2.7 mV), and classified as non-irritant. Drugs co-incorporation up to 1% resulted in encapsulation efficiency >99%, and after 72 h, 25.7% of fenretinide and 57.6% of POH were released. Co-incorporation of POH and fenretinide increased cytotoxicity compared to NLC containing only fenretinide (1.5–4.1-fold in 48 h), reduced cell migration (41.1–88.3%) and increased ROS levels. NLC injection in the subcutaneous tissue of rats generated a depot with local retention of a fluorescent probe for 30 days without local histological changes. Results from this work suggest a potential applicability of the NLCs as a local sustained delivery system for fenretinide and POH.
Malagó et al. (Sun,) studied this question.