Qi Zhang,Mengyuan Xia,Chenxuan Zheng,Yinghong Yang,Junjie Bao,Wenjuan Dai,Xuefeng Mei
Coenzyme Q10 (CoQ10) exists in two forms, an oxidized form and a reduced form. Ubiquinol is the fully reduced form of CoQ10. Compared to the oxidized form, ubiquinol has a much higher biological absorption and better therapeutic effect. However, ubiquinol has an important stability problem which hampers its storage and formulation. It can be easily transformed into its oxidized form—ubiquinone—even at low temperature. In this work, we designed, synthesized, and characterized a new cocrystal of ubiquinol with vitamin B3 nicotinamide (UQ-NC). Compared to the marketed ubiquinol form, the cocrystal exhibited an excellent stability, improved dissolution properties, and higher bioavailability. The cocrystal remained stable for a long period, even when stored under stressed conditions. In the dissolution experiments, the cocrystal generated 12.6 (in SIF) and 38.3 (in SGF) times greater maximum ubiquinol concentrations above that of the marketed form. In addition, in the PK studies, compared to the marketed form, the cocrystal exhibited a 2.2 times greater maximum total coenzyme Q10 concentration and a 4.5 times greater AUC than that of the marketed form.Keywords:ubiquinol;cocrystal;polymorph;stability;bioavailability
Wenting Xu,Yuzhen Yang,Lijuan Liu,Bangli Hu,Yanping Tang,He Ding,Litu Zhang,Piaoping Yang,Chen Wang
Ferroptosis is a newly identified type of regulated cell death characterized by iron-dependent lipid peroxidation. Among the main ferroptosis-suppressing systems, the dihydroorotate dehydrogenase (DHODH)- ubiquinone axis is closely related to mitochondria and energy metabolism, implying that the axis protects cells from oxidative stress damage via the maintenance of redox homeostasis. However, ferroptosis initiation requires a suitable oxidative environment and a breakthrough in redox homeostatic limitations by ferroptosis-suppressing systems. Hence, the nanoparticles are rationally engineered to achieve efficient ferroptosis induction by releasing dual-release free iron and disrupting ferroptosis-suppressing systems. Atovaquone (ATO)-loaded hollow mesoporous etching zeolitic imidazolate framework-67 double-coated iron oxide/calcium phosphate (Fe 3 O 4 /CaP) is conjugated with polyethylene glycol. The external double-coated Fe 3 O 4 /CaP structure enhances the efficiency of multiple reactive oxygen species (ROS) generation promoting oxidative stress. Still, it achieves free iron dual-release to increase the content of unstable iron pools for igniting the ROS storm and lipid peroxidation spark. The release of ATO not only affects the energy metabolism of the mitochondrial respiratory chain by binding to complex III but also downregulates DHODH to restrict the ubiquinol system to disrupt the ferroptosis-suppressing systems. Therefore, the design of this composite nanomedicine provides an approach for inducing ferroptosis and a theoretical basis for clinical ferroptosis anti-tumor trials.
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