Accelerated blood clearance phenomenon upon repeated injection of PEG-modified PLA-nanoparticles.
OBJECTIVE
We recently developed prostaglandin E(1) (PGE(1))-encapsulated nanoparticles, prepared with a poly(lactide) homopolymer (PLA, Mw = 17,500) and monomethoxy poly(ethyleneglycol)-PLA block copolymer (PEG-PLA) (NP-L20). In this study, we tested whether the accelerated blood clearance (ABC) phenomenon is observed with NP-L20 and other PEG-modified PLA-nanoparticles in rats.


METHODS
The plasma levels of PGE(1) and anti-PEG IgM antibody were determined by EIA and ELISA, respectively.


RESULTS
Second injections of NP-L20 were cleared much more rapidly from the circulation than first injections, showing that the ABC phenomenon was induced. This ABC phenomenon, and the accompanying induction of anti-PEG IgM antibody production, was optimal at a time interval of 7 days between the first and second injections. Compared to NP-L20, NP-L33s that were prepared with PLA (Mw = 28,100) and have a smaller particle size induced production of anti-PEG IgM antibody to a lesser extent. NP-L20 but not NP-L33s gave rise to the ABC phenomenon with a time interval of 14 days. NP-L33s showed a better sustained-release profile of PGE(1) than NP-L20.


CONCLUSIONS
This study revealed that the ABC phenomenon is induced by PEG-modified PLA-nanoparticles. We consider that NP-L33s may be useful clinically for the sustained-release and targeted delivery of PGE(1).
Ishihara
Tsutomu
T
Graduate School of Medical and Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Kumamoto, 862-0973, Japan.
Takeda
Miho
M
Sakamoto
Haruka
H
Kimoto
Ayumi
A
Kobayashi
Chisa
C
Takasaki
Naoko
N
Yuki
Kanae
K
Tanaka
Ken-ichiro
K
Takenaga
Mitsuko
M
Igarashi
Rie
R
Maeda
Taishi
T
Yamakawa
Naoki
N
Okamoto
Yoshinari
Y
Otsuka
Masami
M
Ishida
Tatsuhiro
T
Kiwada
Hiroshi
H
Mizushima
Yutaka
Y
Mizushima
Tohru
T
D000818:Animals; D001776:Blood Circulation Time / Q000187:drug effects; D008657:Metabolic Clearance Rate / Q000187:drug effects / Q000502:physiology; D053758:Nanoparticles / Q000008:administration & dosage*; D010316:Particle Size; D011092:Polyethylene Glycols / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors
C542623:monomethoxypolyethyleneglycol-polylactide block copolymer; D011092:Polyethylene Glycols