title: Encapsulation of beraprost sodium in nanoparticles: analysis of sustained release properties, targeting abilities and pharmacological activities in animal models of pulmonary arterial hypertension.
abstract: Prostaglandin I2 (PGI2) and its analogues (such as beraprost sodium, BPS) are beneficial for the treatment of pulmonary arterial hypertension (PAH). The encapsulation of BPS in nanoparticles to provide sustained release and targeting abilities would improve both the therapeutic effect of BPS on PAH and the quality of life of patients treated with this drug. BPS was encapsulated into nanoparticles prepared from a poly(lactic acid) homopolymer and monomethoxy poly(ethyleneglycol)-poly(lactide) block copolymer. The accumulation of nanoparticles in damaged pulmonary arteries was examined using fluorescence-emitting rhodamine S-encapsulated nanoparticles. The monocrotaline-induced PAH rat model and the hypoxia-induced mouse model were used to examine the pharmacological activity of BPS-encapsulated nanoparticles. A nanoparticle, named BPS-NP, was selected among various types of BPS-encapsulated nanoparticles tested; this was based on the sustained release profile in vitro and blood clearance profile in vivo. Fluorescence-emitting rhodamine S-encapsulated nanoparticles were prepared in a similar manner to that of BPS-NP, and showed accumulation and prolonged residence in monocrotaline-damaged pulmonary peripheral arteries. Intravenous administration of BPS-NP (once per week, 20μg/kg) protected against monocrotaline-induced pulmonary arterial remodeling and right ventricular hypertrophy. The extent of this protection was similar to that observed with oral administration (once per day, 100μg/kg) of BPS alone. The once per week intravenous administration of BPS-NP (20μg/kg) also exhibited an ameliorative effect on hypoxia-induced pulmonary arterial remodeling and right ventricular hypertrophy. The beneficial effects of BPS-NP on PAH animal models seem to be mediated by its sustained release and tissue targeting profiles. BPS-NP may be useful for the treatment of PAH patients due to reduced dosages and frequency of BPS administration.
authors.affiliation: Faculty of Pharmacy, Keio University, Tokyo 105-8512, Japan.
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Ishihara
authors.affiliation: Faculty of Pharmacy, Keio University, Tokyo 105-8512, Japan.
authors.forename: Erika
authors.initials: E
authors.lastname: Hayashi
authors.affiliation: Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto 862-0973, Japan.
authors.forename: Shuhei
authors.initials: S
authors.lastname: Yamamoto
authors.affiliation: Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto 862-0973, Japan.
authors.forename: Chisa
authors.initials: C
authors.lastname: Kobayashi
authors.affiliation: Department of Cardiology, Keio University School of Medicine, Tokyo 160-8582, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Tamura
authors.affiliation: Faculty of Pharmacy, Keio University, Tokyo 105-8512, Japan.
authors.forename: Ryoichi
authors.initials: R
authors.lastname: Sawazaki
authors.affiliation: Faculty of Pharmacy, Keio University, Tokyo 105-8512, Japan.
authors.forename: Fumiya
authors.initials: F
authors.lastname: Tamura
authors.affiliation: Faculty of Pharmacy, Keio University, Tokyo 105-8512, Japan.
authors.forename: Kayoko
authors.initials: K
authors.lastname: Tahara
authors.affiliation: Faculty of Pharmacy, Keio University, Tokyo 105-8512, Japan.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Kasahara
authors.affiliation: Department of Chemical Biology and Applied Chemistry, College of Engineering, Nihon University, Fukushima 963-8642, Japan.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Ishihara
authors.affiliation: Division of Drug Delivery System, Institute of Medical Science, St. Marianna University, Kawasaki 216-8512, Japan.
authors.forename: Mitsuko
authors.initials: M
authors.lastname: Takenaga
authors.affiliation: Department of Cardiology, Keio University School of Medicine, Tokyo 160-8582, Japan.
authors.forename: Keiichi
authors.initials: K
authors.lastname: Fukuda
authors.affiliation: Faculty of Pharmacy, Keio University, Tokyo 105-8512, Japan. Electronic address: mizushima-th@pha.keio.ac.jp.
authors.forename: Tohru
authors.initials: T
authors.lastname: Mizushima
mesh_terms: D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects; D003692:Delayed-Action Preparations / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D004195:Disease Models, Animal; D004337:Drug Carriers / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D011464:Epoprostenol / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics; D006976:Hypertension, Pulmonary / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D019344:Lactic Acid / Q000008:administration & dosage / Q000737:chemistry; D008297:Male; D008810:Mice, Inbred C57BL; D016686:Monocrotaline; D053758:Nanoparticles / Q000008:administration & dosage / Q000737:chemistry; D011091:Polyesters; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000737:chemistry; D011108:Polymers / Q000008:administration & dosage / Q000737:chemistry; D011651:Pulmonary Artery / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D017208:Rats, Wistar; D012235:Rhodamines / Q000008:administration & dosage / Q000737:chemistry
chemical_list: D003692:Delayed-Action Preparations; D004337:Drug Carriers; D011091:Polyesters; D011108:Polymers; D012235:Rhodamines; C542623:monomethoxypolyethyleneglycol-polylactide block copolymer; D019344:Lactic Acid; C048081:beraprost; D011092:Polyethylene Glycols; C033616:poly(lactide); D016686:Monocrotaline; D011464:Epoprostenol
keywords: Beraprost sodium; Biodegradable nanoparticle; Encapsulation; Prostaglandin I(2); Pulmonary arterial hypertension