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: Tomoaki Ishihara, Erika Hayashi, Shuhei Yamamoto, Chisa Kobayashi, Yuichi Tamura, Ryoichi Sawazaki, Fumiya Tamura, Kayoko Tahara, Tadashi Kasahara, Tsutomu Ishihara, Mitsuko Takenaga, Keiichi Fukuda, Tohru Mizushima
• Journal: Journal of controlled release : official journal of the Controlled Release Society (J Control Release) Vol. 197 Pg. 97-104 (Jan 10 2015) ISSN: 1873-4995 [Electronic] Netherlands
• PMID: 25449809 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier B.V. All rights reserved.

Chemical References

• Delayed-Action Preparations
• Drug Carriers
• Polyesters
• Polymers
• Rhodamines
• monomethoxypolyethyleneglycol-polylactide block copolymer
• Lactic Acid
• beraprost
• Polyethylene Glycols
• poly(lactide)
• Monocrotaline
• Epoprostenol

Topics

• Animals
• Capillary Permeability (drug effects)
• Delayed-Action Preparations (administration & dosage, chemistry, pharmacokinetics)
• Disease Models, Animal
• Drug Carriers (administration & dosage, chemistry, pharmacokinetics)
• Epoprostenol (administration & dosage, analogs & derivatives, chemistry, pharmacokinetics)
• Hypertension, Pulmonary (drug therapy, metabolism, pathology)
• Lactic Acid (administration & dosage, chemistry)
• Male
• Mice, Inbred C57BL
• Monocrotaline
• Nanoparticles (administration & dosage, chemistry)
• Polyesters
• Polyethylene Glycols (administration & dosage, chemistry)
• Polymers (administration & dosage, chemistry)
• Pulmonary Artery (drug effects, metabolism, pathology)
• Rats, Wistar
• Rhodamines (administration & dosage, chemistry)