Micellization of coenzyme Q by the fungicide caspofungin allows for safe intravenous administration to reach extreme supraphysiological concentrations

Abstract

Coenzyme Q 10 (CoQ 10 ; also known as ubiquinone) is a vital, redox-active membrane component that functions as obligate electron transporter in the mitochondrial respiratory chain, as cofactor in other enzymatic processes and as antioxidant. CoQ 10 supplementation has been widely investigated for treating a variety of acute and chronic conditions in which mitochondrial function or oxidative stress play a role. In addition, it is used as replacement therapy in patients with CoQ deficiency including inborn primary CoQ 10 deficiency due to mutations in CoQ 10 -biosynthetic genes as well as secondary CoQ 10 deficiency, which is frequently observed in patients with mitochondrial disease syndrome and in other conditions. However, despite many tests and some promising results, whether CoQ 10 treatment is beneficial in any indication has remained inconclusive. Because CoQ 10 is highly insoluble, it is only available in oral formulations, despite its very poor oral bioavailability. Using a novel model of CoQ-deficient cells, we screened a library of FDA-approved drugs for an activity that could increase the uptake of exogenous CoQ 10 by the cell. We identified the fungicide caspofungin as capable of increasing the aqueous solubility of CoQ 10 by several orders of magnitude. Caspofungin is a mild surfactant that solubilizes CoQ 10 by forming nano-micelles with unique properties favoring stability and cellular uptake. Intravenous administration of the formulation in mice achieves unprecedented increases in CoQ 10 plasma levels and in tissue uptake, with no observable toxicity. As it contains only two safe components (caspofungin and CoQ 10 ), this injectable formulation presents a high potential for clinical safety and efficacy.

Minimal mitochondrial respiration is required to prevent cell death by inhibition of mTOR signaling in CoQ-deficient cells

“…We decided to explore if this relates to the presence of the intermediate DMQ, whose functional significance for the mutant phenotype is not fully elucidated [ 7 , 9 , 11 , 12 ]. We generated MEFs that lack the expression of both the Coq7 and Pdss2 genes [ 54 ]. Both genes are necessary to make CoQ, but loss of Pdss2 also prevents the synthesis of DMQ [ 54 ].…”

“…Mouse embryonic fibroblasts (MEFs) were routinely cultured in high glucose DMEM (Dulbecco’s modified Eagle’s medium) supplemented with 10% fetal bovine serum (FBS; Thermo Fisher Scientific) and 1% antibiotic/antimycotic mix. Coq7 KO and DKO MEFs were prepared as previously described [ 11 , 54 ]. All cell cultures were confirmed free of mycoplasma using Mycoplasma PCR Detection Kit purchased from ZmTech Scientific Inc. Galactose medium was prepared with glucose-free DMEM (#11966025; Thermo Fisher) and by adding galactose at the final concentration of 10 mM, 1 mM sodium pyruvate, 10% dialyzed FBS (#26400044; Thermo Fisher), and 1 % antibiotic/antimycotic.…”

“…Mitochondrial respiration and glycolysis rates of intact cells were determined using a Seahorse Bioscience XFe24 Extracellular Flux Analyzer as described previously [ 20 , 54 ]. Briefly, cells were seeded at a density of ~30,000 per well, and prior to the measurements, cell medium was replaced with Seahorse XF base medium (supplemented with 10 mM galactose, 2 mM Glutamax, and 1 mM sodium pyruvate) and allowed to equilibrate for 1 h at 37 °C in a non-CO 2 incubator before the start of the assay.…”

Ubisol-Q10, a Nanomicellar and Water-Dispersible Formulation of Coenzyme-Q10 as a Potential Treatment for Alzheimer’s and Parkinson’s Disease

“…Recently Wang and Hekimi (2020) reported a simple two component nanomicellar formation of CoQ 10 with an antifungal drug caspofungin. The researchers discovered that the synthetic drug caspofungin can form stable micelles and delivers better bioavailability of CoQ 10 [ 74 ]. In their formulations, the antifungal pharmaceutical drug is combined with CoQ 10 at a ratio of 0.225 µM:10 or 20 µM and forms wide size distribution micelles with an average size of ~40 nm.…”

Coenzyme Q10: Novel Formulations and Medical Trends

“…Since lipophilicity seems to be the main barrier for the parenteral delivery of CoQ 10 , there is a rising interest in the development of water-soluble CoQ 10 formulations. One of the most famous advances in the field was the formulation of micellar CoQ 10 nanoparticles [ 153 ]. The formation of these hydrophilic particles was mediated by an FDA-approved drug, caspofungin (CF).…”