Synthesis of prostaglandin E(1) phosphate derivatives and their encapsulation in biodegradable nanoparticles.
OBJECTIVE
Prostaglandin E(1) (PGE(1)) is an effective treatment for peripheral vascular diseases. The encapsulation of PGE(1) in nanoparticles for its sustained-release would improve its therapeutic effect and quality of life (QOL) of patients.


METHODS
In order to encapsulate PGE(1) in nanoparticles prepared with a poly(lactide) homopolymer (PLA) and monomethoxy poly(ethyleneglycol)-PLA block copolymer (PEG-PLA), we synthesized a series of PGE(1) phosphate derivatives and tested their efficacy.


RESULTS
Among them, PGE(1) 2-(phosphonooxy)ethyl ester sodium salt (C2) showed the most efficient hydrolysis to yield PGE(1) in human serum. An in vitro platelet aggregation assay showed that C2 inhibited aggregation only after pre-incubation in serum, suggesting that C2 is a prodrug of PGE(1). In vivo, intravenous administration of C2 caused increase in cutaneous blood flow. In the presence of zinc ions, all of the synthesized PGE(1) phosphate derivatives could be encapsulated in PLA-nanoparticles. Use of L-PLA instead of D,L-PLA, and high molecular weight PLA resulted in a slower release of C2 from the nanoparticles.


CONCLUSIONS
We consider that C2-encapsulated nanoparticles prepared with L-PLA and PEG-D,L-PLA have good sustained-release profile of PGE(1), which is useful clinically.
Graduate School of Medical and Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Kumamoto 862-0973, Japan.
Miho
M
Takeda
Taishi
T
Maeda
Tsutomu
T
Ishihara
Haruka
H
Sakamoto
Kanae
K
Yuki
Naoko
N
Takasaki
Fumihiro
F
Nishimura
Takeshi
T
Yamashita
Ken-Ichiro
K
Tanaka
Mitsuko
M
Takenaga
Rie
R
Igarashi
Megumu
M
Higaki
Naoki
N
Yamakawa
Yoshinari
Y
Okamoto
Hisao
H
Ogawa
Masami
M
Otsuka
Yutaka
Y
Mizushima
Tohru
T
Mizushima
D000527:Alprostadil / Q000008:administration & dosage* / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D004337:Drug Carriers / Q000737:chemistry*; D006801:Humans; D006868:Hydrolysis; D019344:Lactic Acid / Q000737:chemistry; D053758:Nanoparticles / Q000737:chemistry*; D010316:Particle Size; D010710:Phosphates / Q000138:chemical synthesis / Q000737:chemistry*; D010974:Platelet Aggregation / Q000187:drug effects; D011091:Polyesters; D011092:Polyethylene Glycols / Q000737:chemistry; D011108:Polymers / Q000737:chemistry; D011355:Prodrugs / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012039:Regional Blood Flow / Q000187:drug effects; D044967:Serum / Q000378:metabolism; D012867:Skin / Q000098:blood supply; D015032:Zinc / Q000737:chemistry
D004337:Drug Carriers; D010710:Phosphates; D011091:Polyesters; D011108:Polymers; D011355:Prodrugs; C542623:monomethoxypolyethyleneglycol-polylactide block copolymer; D019344:Lactic Acid; D011092:Polyethylene Glycols; C033616:poly(lactide); D000527:Alprostadil; D015032:Zinc