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Pharmaceutical Engineering of Fasudil, a Rho-kinase Inhibitor, for the Treatment of Pulmonary Arterial Hypertension (PAH)

Gupta N, Patel B, Nahar K, Absar S, McMurtry IF, Oka M, Komatsu M, Ahsan F.

RDD Europe 2013. Volume 1, 2013: 23-34.

Abstract:

Current anti-PAH medications suffer from a number of limitations including the need for repetitive, frequent administration, lack of pulmonary selectivity, instability, and systemic side effects. We attempted to develop cell-penetrating cyclic peptide, CARSKNKDC (CAR), decorated nanoparticles as targetable and inhalable carriers for delivery of fasudil, a novel anti-PAH drug. We prepared nanosized liposomes and erythrosomes containing fasudil and characterized their physicochemical properties, pharmacokinetics, cellular uptake and pharmacological efficacy in monocrotaline (MCT)-induced PAH rats. We also studied CAR as a targeting moiety to deliver the drug in nanoparticles directly to PAH-induced rat lungs. Data suggested that fasudil encapsulation in lipid nanocarriers was feasible and when incubated with TNF-α-activated rat pulmonary arterial smooth muscle cells (PASMC), CAR-conjugated nanoparticles accumulated predominantly in activated cells. Aerosolized nanoparticles containing fasudil demonstrated ~3.5 times the plasma half-life of fasudil alone producing a longer duration vasodilatory response. Overall, we report a proof-of-principle that an inhalable, targeted, controlled release formulation of fasudil appears viable for the treatment of PAH.