Please cite this article in press as: Ballout, F. et al. Thymoquinone-based nanotechnology for cancer therapy: promises and challenges, Drug Discov Today (2018), https://doi.org/10.1016/j. drudis.2018.01.043 Drug Discovery Today  Volume 00, Number 00  January 2018 REVIEWS Thymoquinone-based nanotechnology for cancer therapy: promises and challenges Farah Ballout 1 ,z , Zeina Habli 1 ,z , Omar Nasser Rahal 2 , Maamoun Fatfat 1 and Hala-Gali Muhtasib 1 ,3 1 Department of Biology and Department of Anatomy, Cell Biology and Physiological Sciences, American University of Beirut, Beirut 1103, Lebanon 2 School of Medicine, Saba University School of Medicine, Saba, Dutch Caribbean 5016121, The Netherlands 3 Department of Biology, Faculty of Arts and Sciences and Center for Drug Discovery, Faculty of Medicine, American University of Beirut, Lebanon Thymoquinone (TQ), the active ingredient of black seed, is a promising anticancer molecule that inhibits cancer cell growth and progression in vitro and in vivo. Despite the promising anticancer activities of TQ, its translation to the clinic is limited by its poor bioavailability and hydrophobicity. As such, we and others encapsulated TQ in nanoparticles to improve its delivery and limit undesirable cytotoxicity. These TQ-nanoparticle formulations showed improved anticancer and anti-inflammatory activities when compared with free TQ. Here, we provide an overview of the various TQ-nanoparticle formulations, highlight their superior efficacy and discuss up-to-date solutions to further enhance TQ bioavailability and anticancer activity, thus improving potential for clinical translation. Introduction Thymoquinone (TQ: 2-isopropyl-5-methylbenzo-1,4-quinone), the main active molecule in Nigella sativa essential oil, is a prom- ising candidate for the treatment of various diseases including cancer. A systematic literature review emphasized TQ as a promi- nent molecule having promising antineoplastic effects against a wide range of solid and liquid tumors in in vitro and in vivo models [1]. What makes TQ interesting is its efficacy and selectivity against cancer cells and lack of toxicity in normal tissues [1]. For instance, TQ has shown anticancer activities against breast cancer cell lines by targeting peroxisome proliferator-activated receptors (PPARs) [2] and nuclear factor (NF)-kB [3]. It has shown chemo-preventive activities through inhibition of cell growth, induction of apoptosis and modulation of transcription factor NF-kB, as well as chemo- sensitizing efficacy to gemcitabine and oxaliplatin in pancreatic cancer [4]. TQ has also been reported to inhibit colon cancer growth and invasion, and induce cell cycle arrest and apoptosis in colon cancer cell culture and animal models [1]. Interestingly, TQ modulates Wnt signaling through glycogen synthase kinase (GSK)-3b activation, b-catenin translocation and reduction of nuclear c-myc. TQ has been shown to mediate reactive oxygen species (ROS) damage in colon cancer, adult T cell leukemia and prostate cancer. In other systems, TQ exhibits strong antioxidant activity by upregulating superoxide dismutase (SOD), catalase (CAT) and glutathione (GPX) (reviewed in Ref. [5]). Many studies have documented the adjuvant ability of TQ to improve the potency of several chemotherapeutic agents by en- hancing their anticancer activity and/or alleviating their toxicity. Owing to these pleiotropic properties, TQ has been shown to alleviate toxicities related to chemotherapeutic agents such as cisplatin nephropathy, doxorubicin cardiotoxicity and acetamin- ophen hepatotoxicity, among others (reviewed in Ref. [1]). The oral administration of TQ was found to be safe in several animal models [6]. In vivo, TQ was not toxic at concentrations higher than its biologically active dose. The LD 50 of TQ in mice and rats ranged between 57 and 104 mg/kg when injected intraperitoneally, and 794 and 870 mg/kg when administered orally – concentrations that are much higher than the dose at which TQ exerted its anticancer activity (<10 mg/kg) (reviewed in Ref. [5]). Unfortu- nately, very few studies investigated the pharmacokinetic and pharmacodynamic characteristics of TQ. One study showed that TQ is reduced into hydroquinone by catalyzing liver enzymes [7] and was detected in the plasma of rats for up to 12 h post oral Reviews  POST SCREEN Corresponding author: Muhtasib, H.-G. (amro@aub.edu.lb) z These authors contributed equally. 1359-6446/ã 2018 Elsevier Ltd. All rights reserved. https://doi.org/10.1016/j.drudis.2018.01.043 www.drugdiscoverytoday.com 1