Formulation and Characterization of Solid Lipid Nanoparticles Loading RF22-c, a Potent and Selective 5-LO Inhibitor, in a Monocrotaline-Induced Model of Pulmonary Hypertension - Liparulo, Angela; Esposito, Renata; Santonocito, Debora; Muñoz-Ramírez, Alejandra; Spaziano, Giuseppe; Bruno, Ferdinando; Xiao, Jianbo; Puglia, Carmelo; Filosa, Rosanna; Berrino, Liberato; D'Agostino, Bruno (Frontiers in Pharmacology, 2020)
Pulmonary Arterial Hypertension (PAH) is a rare but fatal disease characterized by persistent elevated blood pressure in the pulmonary circulation, due to increased resistance to blood flow, through the lungs. Advances in the understanding of the pathobiology of PAH clarify the role of leukotrienes (LTs) that appears to be an exciting new target for disease intervention. Over the years, our group has long investigated in this field, detecting the 1,2-benzoquinone RF-22c as the most powerful and selective competitive inhibitor of the enzyme. With the aim to improve the bioavailability of RF22c and to confirm the role of 5-LO as therapeutic strategy for PAH treatment, we developed a solid lipid nanoparticle (SLNt) loaded with drug. Therefore, in monocrotaline (MCT) rat model of pulmonary arterial hypertension, the role of 5-LO has been investigated, through the formulation of RF22c-SLN. The rats were randomly grouped into control group; MCT group and MCT + RF22c group. After 21 days, all the animals were sacrificed to perform functional and histological evaluations. RF22c-SLN treatment was able to significantly reduce the medial pulmonary arterial pressure (mPAP) and precapillary resistances (R-pre) compared to the MCT group. The MCT induced rise in medial wall thickness of pulmonary arterioles and the cardiomyocytes width were significantly attenuated by RF22c-SNL formulation upon treatment. The results showed that the selective inhibition of 5-LO improved hemodynamic parameters as well as vascular and cardiac remodeling by preventing -induced pulmonary hypertension. The improved sustained release properties and targeting abilities achieved with the innovative nanotechnological approach may be therapeutically beneficial for PAH patients as a consequence of the increase of pharmacological effects and of the possible reduction and/or optimization of the drug frequency of administration.