Peptide–Micelle Hybrids Containing Fasudil for Targeted Delivery to the Pulmonary Arteries and Arterioles to Treat Pulmonary Arterial Hypertension

This study investigates the respirability and efficacy of peptide–micelle hybrid nanoparticles as carriers for inhalational therapy of pulmonary arterial hypertension (PAH). CARSKNKDC (CAR), a cell‐penetrating and lung‐homing peptide, conjugated polyethylene glycol–distearoyl‐phosphoethanolamine micelles containing fasudil, an investigational anti‐PAH drug, were prepared by solvent evaporation method and characterized for various physicochemical properties. The pharmacokinetics and pharmacological efficacy of hybrid particles containing fasudil were evaluated in healthy rats and monocrotaline‐induced PAH rats. CAR micelles containing fasudil had an entrapment efficiency of approximately 58%, showed controlled release of the drug, and were monodispersed with an average size of approximately 14nm. Nuclear magnetic resonance scan confirmed the drug's presence in the core of peptide–micelle hybrid particles. Compared with plain micelles, CAR peptide increased the cellular uptake by approximately 1.7‐fold and extended the drug half‐life by approximately fivefold. The formulations were more prone to accumulate in the pulmonary vasculature than in the peripheral blood, which is evident from the ratio of the extent of reduction of pulmonary and systemic arterial pressures. On the whole, this study demonstrates that peptide–polymer hybrid micelles can serve as inhalational carriers for PAH therapy. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:3743–3753, 2014