Design of multifunctional ethosomes for topical fenretinide delivery and breast cancer chemoprevention

Fenretinide (FENR) is a chemopreventive drug candidate for breast cancer. However, it is an off-the-shelf drug mainly due to its high hydrophobicity and low bioavailability. Herein, we employed a quality by design (QbD) approach to tune ethosomes for innovative FENR topical administration and breast cancer chemoprevention. Ethosomes were selected based on their ability to incorporate poorly soluble drugs and improve their penetration in the skin. Mixed systems (micelles and vesicles) and binary systems (containing ethanol and propylene glycol) were produced by ethanol injection (EI) and film hydration (FH) based on QbD. Skin penetration was assayed using porcine ear skin as model, while cytotoxicity was assayed in tumor (MCF-7) and non-tumor (MCF-10A) cells. For EI, higher values of temperature increased size and PDI; adjustment of the stirring speed and flow rate enabled the obtainment of ethosomes of 200–400 nm (PDI ≤ 0.3) and zeta potential of −18 to −20 mV. For FH, increasing the stirring speed reduced size, but extrusion was necessary to obtain systems of 100–150 nm (PDI < 0.2). The incorporation of FENR was maximized in binary systems, reaching ~50%. Compared to the control solution, mixed and binary systems increased FENR delivery into the epidermis+dermis by 3–4- and 5-fold, respectively. Only binary systems increased drug delivery across the skin and did not reduce the viability of MCF-10A cells, suggesting tolerability. In conclusion, QbD enabled the optimization of ethosomes, and FENR incorporation into an aqueous-based delivery system capable of enhancing skin penetration without compromising the in vitro cytotoxicity and selectivity against cancer cells.