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.

Nanoparticle-Mediated Drug Delivery System for Pulmonary Arterial Hypertension

“…Pitavastatin,(24) nuclear factor kappaB decoy, (25) imatinib, (26) prostacyclin analog, (27,28), fasudil, (29) and antimiRNA-145-incorporated NPs, (30) have been reported to be effective in animal models of PH (Table 1). In this review, we summarize results of recent studies using prostacyclin analog-incorporated NPs (27,28) and imatinib-incorporated NPs. (26) NF-kB, nuclear factor kappaB; PLGA, poly(lactide-co-glycolide); PEG-PLGA, poly-(ethyleneglycol)-PLGA;…”

Biodegradable Nanoparticles for Delivering Drugs and Silencing Multiple Genes or Gene activation in Diabetic Nephropathy

“…Targeting PLCγ in DN [2] : Inhibitors of p38MAPK signaling Pathway [2,31] : Animal model study Beraprost Sodium: In investigational study Beraprost sodium enhanced lipid profile, blood glucose, 24 hour urinary protein p38MAPK signaling pathway is activated in diabetic kidney.…”

“…Further study is needed to understand the beneficial effect of inhibiting pathway. Currently nanoparticles of Beraprost are tested in animal models with pulmonary hypertension [31] on similar lines it could be tested in DN.…”

Novel therapeutic approaches for pulmonary arterial hypertension: Unique molecular targets to site-specific drug delivery

“…Higher accumulation and prolonged residence time in the pulmonary arteries. Effective against MCT-and hypoxiainduced pulmonary arterial remodeling and right ventricular hypertrophy [128] A C C E P T E D M A N U S C R I P T…”

“…Although the formulation was not tested in animal PAH model, it was suggested that nanoparticles could be potential carriers for targeted PAH therapy. Later, the same group developed beraprost loaded PLGA nanoparticles and tested in MCT-induced and hypoxia-induced mouse PAH model for their pharmacological activity [128]. Beraprost-loaded nanoparticles showed higher accumulation and prolonged residence time in the damaged pulmonary arteries.…”