TY - JOUR
T1 - Early controlled release of peroxisome proliferator-activated receptor β/δ agonist GW501516 improves diabetic wound healing through redox modulation of wound microenvironment
AU - Wang, Xiaoling
AU - Sng, Ming Keat
AU - Foo, Selin
AU - Chong, Han Chung
AU - Lee, Wei Li
AU - Tang, Mark Boon Yang
AU - Ng, Kee Woei
AU - Luo, Baiwen
AU - Choong, Cleo
AU - Wong, Marcus Thien Chong
AU - Tong, Benny Meng Kiat
AU - Chiba, Shunsuke
AU - Loo, Say Chye Joachim
AU - Zhu, Pengcheng
AU - Tan, Nguan Soon
N1 - Publisher Copyright:
© 2014 Elsevier B.V. All rights reserved.
PY - 2015/1/10
Y1 - 2015/1/10
N2 - Diabetic wounds are imbued with an early excessive and protracted reactive oxygen species production. Despite the studies supporting PPARβ/δ as a valuable pharmacologic wound-healing target, the therapeutic potential of PPARβ/δ agonist GW501516 (GW) as a wound healing drug was never investigated. Using topical application of polymer-encapsulated GW, we revealed that different drug release profiles can significantly influence the therapeutic efficacy of GW and consequently diabetic wound closure. We showed that double-layer encapsulated GW microparticles (PLLA:PLGA:GW) provided an earlier and sustained dose of GW to the wound and reduced the oxidative wound microenvironment to accelerate healing, in contrast to single-layered PLLA:GW microparticles. The underlying mechanism involved an early GW-mediated activation of PPARβ/δ that stimulated GPx1 and catalase expression in fibroblasts. GPx1 and catalase scavenged excessive H2O2 accumulation in diabetic wound beds, prevented H2O2-induced ECM modification and facilitated keratinocyte migration. The microparticles with early and sustained rate of GW release had better therapeutic wound healing activity. The present study underscores the importance of drug release kinetics on the therapeutic efficacy of the drug and warrants investigations to better appreciate the full potential of controlled drug release.
AB - Diabetic wounds are imbued with an early excessive and protracted reactive oxygen species production. Despite the studies supporting PPARβ/δ as a valuable pharmacologic wound-healing target, the therapeutic potential of PPARβ/δ agonist GW501516 (GW) as a wound healing drug was never investigated. Using topical application of polymer-encapsulated GW, we revealed that different drug release profiles can significantly influence the therapeutic efficacy of GW and consequently diabetic wound closure. We showed that double-layer encapsulated GW microparticles (PLLA:PLGA:GW) provided an earlier and sustained dose of GW to the wound and reduced the oxidative wound microenvironment to accelerate healing, in contrast to single-layered PLLA:GW microparticles. The underlying mechanism involved an early GW-mediated activation of PPARβ/δ that stimulated GPx1 and catalase expression in fibroblasts. GPx1 and catalase scavenged excessive H2O2 accumulation in diabetic wound beds, prevented H2O2-induced ECM modification and facilitated keratinocyte migration. The microparticles with early and sustained rate of GW release had better therapeutic wound healing activity. The present study underscores the importance of drug release kinetics on the therapeutic efficacy of the drug and warrants investigations to better appreciate the full potential of controlled drug release.
KW - Controlled release
KW - Diabetic wound healing
KW - GW501516
KW - Hydrogen peroxide
KW - Microparticle
KW - Peroxisome proliferator-activated receptor beta/delta
UR - http://www.scopus.com/inward/record.url?scp=84911488199&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84911488199&partnerID=8YFLogxK
U2 - 10.1016/j.jconrel.2014.11.001
DO - 10.1016/j.jconrel.2014.11.001
M3 - Article
C2 - 25449811
AN - SCOPUS:84911488199
SN - 0168-3659
VL - 197
SP - 138
EP - 147
JO - Journal of Controlled Release
JF - Journal of Controlled Release
ER -
