Low Dose Curcumin Administered in Hyaluronic Acid-Based Nanocapsules Induces Hypotensive Effect in Hypertensive Rats

Background: Vascular drug delivery becomes a promising direction in the development of novel therapeutic strategies in the treatment of cardiovascular pathologies, such as hypertension. However, targeted delivery of hydrophobic substances, with poor bioavailability, remains a challenge. Here, we described the hypotensive effects of a low dose of curcumin delivered to the vascular wall using hyaluronic acid-based nanocapsules. Methods: The group of hypertensive TGR(m-Ren2)27 rats, was administrated respectively with the vehicle, curcumin solution or curcumin delivered using hyaluronic acid-based nanocapsules (HyC12-Cur), for 7 days each, maintaining the wash-out period between treatments. Arterial blood pressure (systolic - SBP, diastolic - DBP) and heart rate (HR) were monitored continuously using a telemetry system (Data Science International), and Mean Arterial Pressure (MAP) was calculated from SBP and DBP. Results: In hypertensive rats, a low dose of curcumin (4.5 mg/kg) administrated in HyC12-Cur for 7 days resulted in a gradual inhibition of SBP, DBP and MAP increase without an effect on HR. At the end of HyC12-Cur - based treatment changes in SBP, DBP and MAP amounted to -2.0 +/- 0.8 mmHg, -3.9 +/- 0.7 mmHg and -3.3 +/- 0.7 mmHg, respectively. In contrast, the administration of a curcumin solution (4.5 mg/kg) did not result in a significant hypotensive effect and the animals constantly developed hypertension. Vascular delivery of capsules with curcumin was confirmed using newly developed fluorine-rich nanocapsules (HyFC10-PFOB) with a shell based on a HA derivative and similar size as HyC12-Cur. HyFC10-PFOB gave fluorine signals in rat aortas analyzed ex vivo with a (19 ) NMR technique after a single intragastric administration. Conclusion: These results suggest that nanocapsules based on hyaluronic acid, the ubiquitous glycosaminoglycan of the extracellular matrix and an integral part of endothelial glycocalyx, may represent a suitable approach to deliver hydrophobic, poorly bioavailable compounds, to the vascular wall.