title: Early controlled release of peroxisome proliferator-activated receptor β/δ agonist GW501516 improves diabetic wound healing through redox modulation of wound microenvironment.
abstract: 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.
authors.affiliation: School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551.
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Wang
authors.affiliation: School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551.
authors.forename: Ming Keat
authors.initials: MK
authors.lastname: Sng
authors.affiliation: School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551.
authors.forename: Selin
authors.initials: S
authors.lastname: Foo
authors.affiliation: School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551.
authors.forename: Han Chung
authors.initials: HC
authors.lastname: Chong
authors.affiliation: School of Materials Science and Engineering, Nanyang Technological University, Singapore 639798.
authors.forename: Wei Li
authors.initials: WL
authors.lastname: Lee
authors.affiliation: National Skin Centre, 1 Mandalay Road, Singapore 308205.
authors.forename: Mark Boon Yang
authors.initials: MB
authors.lastname: Tang
authors.affiliation: School of Materials Science and Engineering, Nanyang Technological University, Singapore 639798.
authors.forename: Kee Woei
authors.initials: KW
authors.lastname: Ng
authors.affiliation: School of Materials Science and Engineering, Nanyang Technological University, Singapore 639798.
authors.forename: Baiwen
authors.initials: B
authors.lastname: Luo
authors.affiliation: School of Materials Science and Engineering, Nanyang Technological University, Singapore 639798.
authors.forename: Cleo
authors.initials: C
authors.lastname: Choong
authors.affiliation: Tan Tock Seng Hospital, 11 Jalan Tan Tock Seng, Singapore 308433.
authors.forename: Marcus Thien Chong
authors.initials: MT
authors.lastname: Wong
authors.affiliation: Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University, 21 Nanyang Link, Singapore 637371.
authors.forename: Benny Meng Kiat
authors.initials: BM
authors.lastname: Tong
authors.affiliation: Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University, 21 Nanyang Link, Singapore 637371.
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Chiba
authors.affiliation: School of Materials Science and Engineering, Nanyang Technological University, Singapore 639798.
authors.forename: Say Chye Joachim
authors.initials: SC
authors.lastname: Loo
authors.affiliation: School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551. Electronic address: pczhu@ntu.edu.sg.
authors.forename: Pengcheng
authors.initials: P
authors.lastname: Zhu
authors.affiliation: School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551; Institute of Molecular and Cell Biology, 61 Biopolis Drive, Proteos, Singapore 138673. Electronic address: nstan@ntu.edu.sg.
authors.forename: Nguan Soon
authors.initials: NS
authors.lastname: Tan
mesh_terms: D000818:Animals; D002374:Catalase / Q000378:metabolism; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D003692:Delayed-Action Preparations; D003920:Diabetes Mellitus / Q000188:drug therapy / Q000378:metabolism; D016503:Drug Delivery Systems; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D005979:Glutathione Peroxidase / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D019344:Lactic Acid / Q000737:chemistry; D008297:Male; D051379:Mice; D008855:Microscopy, Electron, Scanning; D010084:Oxidation-Reduction; D047494:PPAR delta / Q000819:agonists*; D048068:PPAR-beta / Q000819:agonists*; D011091:Polyesters; D011100:Polyglycolic Acid / Q000737:chemistry; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011108:Polymers / Q000737:chemistry; D017382:Reactive Oxygen Species / Q000378:metabolism; D013844:Thiazoles / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D014945:Wound Healing / Q000187:drug effects*
chemical_list: D003692:Delayed-Action Preparations; C425931:GW 501516; D047494:PPAR delta; D048068:PPAR-beta; D011091:Polyesters; D011108:Polymers; D017382:Reactive Oxygen Species; D013844:Thiazoles; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; C033616:poly(lactide); D003094:Collagen; D006861:Hydrogen Peroxide; D002374:Catalase; D005979:Glutathione Peroxidase
keywords: Controlled release; Diabetic wound healing; GW501516; Hydrogen peroxide; Microparticle; Peroxisome proliferator-activated receptor beta/delta