TY - JOUR
T1 - Synthesis of prostaglandin E1 phosphate derivatives and their encapsulation in biodegradable nanoparticles
AU - Takeda, Miho
AU - Maeda, Taishi
AU - Ishihara, Tsutomu
AU - Sakamoto, Haruka
AU - Yuki, Kanae
AU - Takasaki, Naoko
AU - Nishimura, Fumihiro
AU - Yamashita, Takeshi
AU - Tanaka, Ken Ichiro
AU - Takenaga, Mitsuko
AU - Igarashi, Rie
AU - Higaki, Megumu
AU - Yamakawa, Naoki
AU - Okamoto, Yoshinari
AU - Ogawa, Hisao
AU - Otsuka, Masami
AU - Mizushima, Yutaka
AU - Mizushima, Tohru
N1 - Funding Information:
We thank to Daiichi Fine Chemical Co., Ltd (Takaoka, Japan) for supplying PE1 (compound 4). This work was supported by Grants-in-Aid for Scientific Research from the Ministry of Health, Labour, and Welfare of Japan, as well as the Japan Science and Technology Agency and Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology, Japan.
PY - 2009/7
Y1 - 2009/7
N2 - Purpose: Prostaglandin E1 (PGE1) is an effective treatment for peripheral vascular diseases. The encapsulation of PGE1 in nanoparticles for its sustained-release would improve its therapeutic effect and quality of life (QOL) of patients. Methods: In order to encapsulate PGE1 in nanoparticles prepared with a poly(lactide) homopolymer (PLA) and monomethoxy poly(ethyleneglycol)-PLA block copolymer (PEG-PLA), we synthesized a series of PGE1 phosphate derivatives and tested their efficacy. Results: Among them, PGE1 2-(phosphonooxy)ethyl ester sodium salt (C2) showed the most efficient hydrolysis to yield PGE1 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 PGE1. In vivo, intravenous administration of C2 caused increase in cutaneous blood flow. In the presence of zinc ions, all of the synthesized PGE1 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 PGE1, which is useful clinically.
AB - Purpose: Prostaglandin E1 (PGE1) is an effective treatment for peripheral vascular diseases. The encapsulation of PGE1 in nanoparticles for its sustained-release would improve its therapeutic effect and quality of life (QOL) of patients. Methods: In order to encapsulate PGE1 in nanoparticles prepared with a poly(lactide) homopolymer (PLA) and monomethoxy poly(ethyleneglycol)-PLA block copolymer (PEG-PLA), we synthesized a series of PGE1 phosphate derivatives and tested their efficacy. Results: Among them, PGE1 2-(phosphonooxy)ethyl ester sodium salt (C2) showed the most efficient hydrolysis to yield PGE1 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 PGE1. In vivo, intravenous administration of C2 caused increase in cutaneous blood flow. In the presence of zinc ions, all of the synthesized PGE1 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 PGE1, which is useful clinically.
KW - Biodegradable nanoparticles
KW - Encapsulation
KW - Prostaglandin E
KW - Zinc
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U2 - 10.1007/s11095-009-9891-5
DO - 10.1007/s11095-009-9891-5
M3 - Article
C2 - 19415470
AN - SCOPUS:67349083550
VL - 26
SP - 1792
EP - 1800
JO - Pharmaceutical Research
JF - Pharmaceutical Research
SN - 0724-8741
IS - 7
ER -
