title: Intratracheal Administration of Prostacyclin Analogue-incorporated Nanoparticles Ameliorates the Development of Monocrotaline and Sugen-Hypoxia-induced Pulmonary Arterial Hypertension.
abstract: Nanoparticles (NPs) have been used as novel drug delivery systems. Drug-incorporated NPs for local delivery might optimize the efficacy and minimize the side effects of drugs. Intravenous prostacyclin improves long-term survival in patients with pulmonary arterial hypertension (PAH), but it causes serious side effects such as catheter-related infections. We investigated the efficacy and safety of intratracheal administration of a prostacyclin analogue, beraprost (BPS), incorporated NPs in Sugen-hypoxia-normoxia and monocrotaline rat models of PAH and in human PAH pulmonary arterial smooth muscle cells (PASMCs). After a single administration, BPS NPs significantly decreased right ventricular pressure, right ventricular hypertrophy, and pulmonary artery muscularization in the 2 rat models. BPS NPs significantly improved the survival rate in the monocrotaline rat model. No infiltration of inflammatory cells, hemorrhage, or fibrosis was found in the liver, kidney, spleen, and heart after the administration of BPS NPs. No liver or kidney dysfunction was found in the blood examinations. BPS and BPS NPs significantly inhibited the proliferation of human PAH PASMCs after 24 hours of treatment. BPS NPs significantly continued to inhibit the proliferation of human PAH PASMCs at 24 hours after the removal of BPS NPs. BPS NPs significantly induced apoptosis in PAH PASMCs compared to that in non-PAH PASMCs. Intratracheal administration of BPS NPs ameliorates pulmonary hypertension in PAH rat models by a sustained antiproliferative effect and a proapoptotic effect on PAH PASMCs.
authors.affiliation: *Department of Cardiovascular Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan; †Department of Clinical Science, National Hospital Organization Okayama Medical Center, Okayama, Japan; and ‡Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Akagi
authors.forename: Kazufumi
authors.initials: K
authors.lastname: Nakamura
authors.forename: Hiromi
authors.initials: H
authors.lastname: Matsubara
authors.forename: Megumi
authors.initials: M
authors.lastname: Kondo
authors.forename: Daiji
authors.initials: D
authors.lastname: Miura
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Matoba
authors.forename: Kensuke
authors.initials: K
authors.lastname: Egashira
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ito
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D015687:Cell Hypoxia; D049109:Cell Proliferation / Q000187:drug effects; D002648:Child; D004195:Disease Models, Animal; D016503:Drug Delivery Systems; D011464:Epoprostenol / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D005260:Female; D006801:Humans; D006976:Hypertension, Pulmonary / Q000517:prevention & control*; D017380:Hypertrophy, Right Ventricular / Q000188:drug therapy / Q000473:pathology; D008297:Male; D016686:Monocrotaline / Q000633:toxicity; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D053758:Nanoparticles; D011651:Pulmonary Artery / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D055815:Young Adult
chemical_list: C048081:beraprost; D016686:Monocrotaline; D011464:Epoprostenol