Sustained delivery of
sphingosine-1-phosphate (S1P) by using PLGA microparticles
stimulates post-ischemic angiogenesis
Xun Qi, Naotoshi
Sugimoto, Osamu Oyama, Kiyomi Mizugishi, Noriko Takuwa, and
Yoh Takuwa
ABSTRACT
S1P plays a critical
role in vascular maturation in vivo during the mammalian development.
Recently, we demonstrated for the first time that S1P
stimulated neo-angiogenesis in ischemic hindlimbs of mice.
In the previous study, we daily injected S1P solution
locally into the hindlimb muscle. In the present study, we
successfully generated a slow release type of S1P by taking
advantage of three different
poly(lactic-co-glycolic-acid)(PLGAs), and tested its
efficacy in the mouse ischemic hindlimb where femoral
artery was ligated and removed unilaterally. The amounts of
S1P released from S1P-containing PLGA microparticles in a
physiological medium were quite constant over 15 days in
PLGA 5005. In contrast, S1P release from PLGA7505 and
PLGA7510 with longer half lives than PLGA5005 sharply
declined after the initial burst. Local injections of
PLGA5005-S1P microparticles every 3 days, but not
PLGA7505-S1P or PLGA7510-S1P, into ischemic muscle
stimulated the blood flow recovery over 28 days after
femoral arteriectomy, as determined with a laser Doppler
imager. PLGA5005-S1P was effective in the wide range of
doses. In contrast, PLGA7505-S1P and PLGA7510-S1P were less
effective or non-effective in stimulating the blood flow
recovery. Injections of PLGA5005-S1P stimulated
angiogenesis, as determined with anti-CD31
immunohistochemistry. These results suggested that
PLGA5005-S1P could be potentially useful as a therapeutic
agent for stimulating post-ischemic
angiogenesis.