Thymoquinone (2-isopropyl-5-methyl-1,4-benzoquinone) is a herbal-derived drug with potential chemopreventive and chemotherapeutic activity. However, thymoquinone suffers from high hydrophobicity causing poor solubility which limits its bioavailability and high lipophilicity causing poor formulation characteristics. Liposomes are versatile drug carriers that can be used to solve problems of drug solubility, instability, and bio-distribution. In this study, we were able to prepare thymoquinone-loaded liposomes (TQ-LP) and thymoquinone loaded in liposomes modified with Triton X-100 (XLP) with diameters of about 100 nm, and entrapment efficiency of more than 90% for TQ-LP and of 49.6% for XLP. The TQ-LP liposomes were effective in suppressing the proliferation of breast cancer cell lines MCF-7 and T47D, and at the same time exerting very low toxicity on normal periodontal ligament fibroblast. Altogether, this report describes the first successful encapsulation of thymoquinone into liposome; which maintains stability, improves bioavailability and maintains its anticancer activity.

A new combination strategy of an active loading and active targeting approach was applied in this work. The liposomes actively loaded with Curcumin (CRM) (Lip_CRM) were decorated with cholesterol tagged-anti-nucleolin AS1411 aptamer (NCL) via a new post-insertion approach, utilizing the cholesterol as a wedge to incorporate aptamer into the surface of the liposome bilayer. A successful NCL post-insertion was verified by agarose gel electrophoresis and dynamic light scattering (DLS). The cellular uptake of Apt_NCL-Lip was investigated using flow cytometry and Confocal Laser Scanning Microscopy (CLSM) on two different human breast cancer cell lines (MCF-7 and MDA-MB-231). The uptake and cytotoxicity of loaded CRM were investigated using flow cytometry and MTT assay. Our results showed successful post insertion of NCL aptamer to the surface of Lip. Also, higher cellular uptake was noted for Apt_NCL-Alexa-Lip_Rhod compared to blank Lip_Rhod in both cell lines. Moreover, CLSM showed prominent endocytosis and uptake of Apt_NCL-Alexa–Lip_Rhod into the cytoplasm of breast cancer cells. Furthermore, the results showed a significant increase in the uptake and cytotoxicity of Apt_NCL-Lip_CRM compared to Lip_CRM in both cell lines. Overall, our results demonstrate a successful post-insertion of cholesterol-tagged aptamer into liposomes and the possible combination between active loading and active targeting.

Combinatorial therapeutic strategies to eradicate tumors can be superior to a single therapeutic modality. Docetaxel (DT) has been approved for the treatment of local or metastasized breast cancer alone or in combination with other chemotherapeutic agents. Thymoquinone (TQ) originated from the seeds of Nigella Sativa plant has been reported to possess in vitro and in vivo antitumor activity against variety of tumors. In the current study, we have investigated the synergistic anticancer efficacy of a novel combination of DT and TQ on MCF7 breast cancer cell line using MTT cell viability assay. Moreover, this study describes for the first time the co-encapsulation of DT and TQ into PEGylated liposomes. The results showed that the combination of DT and TQ resulted in significant synergistic cytotoxicity compared to DT and TQ alone. Moreover, DT and TQ have been successfully co-encapsulated into PEGylated liposomes with higher encapsulation efficiency compared to DT and TQ alone. In conclusion, DT and TQ combination poses a synergistic effect and may aid in decreasing the required doses of DT. Also, the co-encapsulation of DT and TQ into PEGylated liposomes can provide a promising DT and TQ delivery system into cancer cells.

The neonatal Fc receptor (FcRn) rescues albumin and IgG from degradation following endocytosis and thereby extends the half-life of these plasma proteins. However, the pathways for the uptake of these soluble FcRn ligands, and the recycling itinerary of the FcRn–ligand complexes, have not been identified in primary cells. Here, we have defined the recycling of human albumin and IgG in primary mouse macrophages selectively expressing the human FcRn. Albumin is internalised by macropinocytosis; in the absence of FcRn, internalised albumin is rapidly degraded, while in the presence of FcRn albumin colocalises to SNX5-positive membrane domains and is partitioned into tubules emanating from early macropinosomes for delivery in transport carriers to the plasma membrane. Soluble monomeric IgG was also internalised by macropinocytosis and rapidly recycled by the same pathway. In contrast, the fate of IgG bound to surface Fcγ receptors differed from monomeric IgG endocytosed by macropinocytosis. Overall, our findings identify a rapid recycling pathway for FcRn ligands from early macropinosomes to the cell surface of primary cells.

Quinones are a class of cyclic organic compounds that are widely distributed in nature and have been shown to exhibit anti-inflammatory, antioxidant, and anticancerous activities. However, the molecular mechanisms/signaling by which these molecules exert their effect are still not fully understood. In this study, a group of quinone-derived compounds were examined for their potential inhibitory effect against human IRAK1 and IRAK4 kinases in vitro. We have identified five compounds: 1,4-naphthoquinone, emodin, shikonin, plumbagin, and menadione (vitamin K3) as active and selective inhibitors of human IRAK1 enzyme in vitro. The biochemical binding and molecular interactions between the active compounds and IRAK1’s catalytic site were demonstrated in silico using structural-based docking and dynamic simulation analysis. Also, 1,4-naphthoquinone was found to effectively inhibit the growth of cancer cell lines overexpressing IRAK1. Furthermore, 1,4-naphthoquinone potently suppressed the production and secretion of key proinflammatory cytokine proteins IL-8, IL-1β, IL-10, TNF-α, and IL-6 in LPS-stimulated PMA-induced human THP-1 macrophages. In conclusion, 1,4-naphthoquinone is an effective inhibitor of IRAK1 kinases and their mediated inflammatory cytokines production in LPS-stimulated PMA-induced human THP-1 macrophages.