Rapid Replenishment of Phylloquinone in the Plasma and Liver Using Hyaluronan-Based Nanocapsules Reverses Endothelial Dysfunction in Mice.

Abstract

Introduction: As vitamin K₁ (phylloquinone, PK) displays vasoprotective effect, low dietary intake and poor bioavailability of PK may result in insufficient systemic levels for maintaining vascular health. This study aimed to test whether PK in hyaluronan-based nanocapsules (PK-Oil-HyC12) improves PK pharmacokinetics and endothelial function compared to PK in oil emulsion (PK-Oil).

Methods: PK pharmacokinetics in plasma, liver and aorta were analysed after single, oral administration of PK (10 mg/kg) in oil (PK-Oil) or encapsulated in hyaluronan-based nanocapsules with oil core (PK-Oil-HyC12) in mice using liquid chromatography-tandem mass spectrometry with atmospheric pressure chemical ionization method. PK-Oil-HyC12 absorption and nanocapsules distribution in lymphatic system was determined using a cycloheximide-based chylomicron flow blockage and intravital confocal microscopy. The endothelial function was analyzed in vivo by MRI in mice with dietary PK deficiency after 7-day supplementation with PK-Oil or PK-Oil-HyC12 (0.5 mg PK/kg).

Results: After a single, oral dose of PK-Oil-HyC12 in mice total exposure of PK (AUC values) was 2-4 times higher as compared to PK-Oil in plasma and liver, with no difference in PK content in the aorta. The efficient absorption and distribution of nanocapsules occurred mainly via a chylomicron-independent lymphatic route. Importantly, 7-day PK-Oil-HyC12 supplementation restored impaired endothelium-dependent vasodilation in the aorta of PK-deficient mice, while PK-Oil was ineffective.

Conclusion: The improved bioavailability of PK, when administered in the form of hyaluronan-based nanocapsules, afforded the rapid replenishment of systemic PK and the reversal of endothelial dysfunction induced by low PK levels.