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.

Engineering of blended nanoparticle platform for delivery of mitochondria-acting therapeutics

“…The development of technologies for targeted delivery of known mitochondria-acting therapeutics to the site of mitochondria has the potential to launch new therapeutic approaches for mitochondria-related diseases (8). Currently, only a handful of metal oxide-or liposomal-based carriers are known to deliver payloads to the mitochondria of cells (SI Appendix, Table S1) (9)(10)(11)(12)(13)(14)(15)(16)(17), none of which has demonstrated optimization and application of the FDA-approved biodegradable PLGA-based NP system in delivering known mitochondriaacting therapeutics to their precise destination.…”

Miktoarm Star Micelles Containing Curcumin Reduce Cell Viability of Sensitized Glioblastoma

“…Miktoarm micelles were prepared by the co-solvent evaporation method [22]. Specific weights of the polymer and drug (drug/polymer ratio of 0-50 wt.…”

“…The synthesis of A 2 B miktoarm star polymers was achieved by an adaptation of our previously published procedure, using a core with orthogonal functionalities (1), and Cu(I) catalyzed alkyne azide click reaction in sequence with ring opening polymerization (ROP), ( Figure 1A) [22]. The azide terminated-PEG 750 was synthesized starting from commercially available PEG mono methyl ether [25].…”

“…The size and polydisperisty index of the micelles prepared in water by the co-solvent evaporation method were studied by DLS [22]. Table 2 shows the hydrodynamic diameter (DH) for both curcuminloaded and unloaded micelles of (PEG 750 ) 2 -PCL miktoarms of different molecular weights.…”

“…Miktoarm stars can be synthetically articulated using click chemistry for enhancing drug incorporation into their micelles [15][16][17][18][19][20]. Amphiphilic miktoarm star polymers spontaneously form nanoscale core/shell structures in aqueous environments, where hydrophobic polymer arms form the core of the micelles and hydrophilic ones form corona [21,22]. The core of these micelles can be used to load hydrophobic drugs in order to overcome their insolubility in water, control their release and protect them from rapid degradation and metabolism in the body.…”