title: Design and evaluation of multifunctional nanocarriers for selective delivery of coenzyme Q10 to mitochondria.
abstract: Impairments of mitochondrial functions have been associated with failure of cellular functions in different tissues, leading to various pathologies. We report here a mitochondria-targeted nanodelivery system for coenzyme Q10 (CoQ10) that can reach mitochondria and deliver CoQ10 in adequate quantities. Multifunctional nanocarriers based on ABC miktoarm polymers (A = poly(ethylene glycol (PEG), B = polycaprolactone (PCL), and C = triphenylphosphonium bromide (TPPBr)) were synthesized using a combination of click chemistry with ring-opening polymerization, self-assembled into nanosized micelles, and were employed for CoQ10 loading. Drug loading capacity (60 wt %), micelle size (25-60 nm), and stability were determined using a variety of techniques. The micelles had a small critical association concentration and were colloidally stable in solution for more than 3 months. The extraordinarily high CoQ10 loading capacity in the micelles is attributed to good compatibility between CoQ10 and PCL, as indicated by the low Flory-Huggins interaction parameter. Confocal microscopy studies of the fluorescently labeled polymer analog together with the mitochondria-specific vital dye label indicated that the carrier did indeed reach mitochondria. The high CoQ10 loading efficiency allowed testing of micelles within a broad concentration range and provided evidence for CoQ10 effectiveness in two different experimental paradigms: oxidative stress and inflammation. Combined results from chemical, analytical, and biological experiments suggest that the new miktoarm-based carrier provides a suitable means of CoQ10 delivery to mitochondria without loss of drug effectiveness. The versatility of the click chemistry used to prepare this new mitochondria-targeting nanocarrier offers a widely applicable, simple, and easily reproducible procedure to deliver drugs to mitochondria or other intracellular organelles.
authors.affiliation: Department of Chemistry, McGill University, Montreal, Quebec, H3A 2K6, Canada.
authors.forename: Anjali
authors.initials: A
authors.lastname: Sharma
authors.forename: Ghareb M
authors.initials: GM
authors.lastname: Soliman
authors.forename: Noura
authors.initials: N
authors.lastname: Al-Hajaj
authors.forename: Rishi
authors.initials: R
authors.lastname: Sharma
authors.forename: Dusica
authors.initials: D
authors.lastname: Maysinger
authors.forename: Ashok
authors.initials: A
authors.lastname: Kakkar
mesh_terms: D000818:Animals; D002460:Cell Line; D016503:Drug Delivery Systems; D015195:Drug Design; D051379:Mice; D017628:Microglia / Q000166:cytology / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism*; D053758:Nanoparticles / Q000737:chemistry*; D009943:Organophosphorus Compounds / Q000737:chemistry; D011091:Polyesters / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry; D014451:Ubiquinone / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D009943:Organophosphorus Compounds; D011091:Polyesters; D014451:Ubiquinone; C016240:polycaprolactone; D011092:Polyethylene Glycols; C024989:coenzyme Q10