Co-delivery of exemestane and thymoquinone via nanostructured lipid carriers for efficient breast cancer therapy

Owing to the poor therapeutic outcomes with a single chemotherapeutic agent, the co-delivery of agents for achieving high efficacy in managing breast cancer has been gaining a lot of interest lately. The objective of the present study was the fabrication and optimization of nanostructured lipid carriers (NLCs) for the co-delivery of lipophilic chemotherapeutics, namely, exemestane (EXE) and thymoquinone (THY) via oral route with the aim to improve their efficacy in breast cancer. The EXE and THY co-loaded NLCs (EXE-THY-NLCs) were formulated by ultrasonication technique and were further optimized by Box-Behnken Design (BBD). The optimized EXE-THY-NLCs exhibited particle size (268.2 +/- 7.42 nm), PDI (0.155 +/- 0.04) and zeta potential (-30.7 mV) within the desired limits while the % entrapment efficiency (% EE) of 76.2 +/- 3.14%, and 75.1 +/- 2.87% was obtained for EXE and THY, respectively. The results of in vitro drug release studies and the ex vivo permeation studies revealed the sustained release pattern and enhanced depth of permeation owing to the nanometric size range of EXE-THY-NLCs. The DPPH antioxidant assay revealed an augmented antioxidant potential of EXE-THY-NLCs. Furthermore, higher cellular internalization and enhanced killing effect (****p < 0.0001) were observed with EXE-THY-NLCs on the MCF-7 cells compared to the individual and combined drug suspensions. The results of confocal laser scanning microscopy (CLSM) revealed a 2-fold enhancement in the penetration of the Rhodamine-B labelled NLCs to deeper layers through the intestine of Wistar rats compared to the plain Rhodamine-B solution. Moreover, acute toxicity studies carried out on Wistar rats showed the safety of the developed NLCs for oral administration in breast cancer. The present study paves a new paradigm for the co-delivery of synthetic and herbal agents in NLCs for enhanced therapeutic effect in breast cancer treatment.