title: Hydrogen peroxide-activatable antioxidant prodrug as a targeted therapeutic agent for ischemia-reperfusion injury.
abstract: Overproduction of hydrogen peroxide (H2O2) causes oxidative stress and is the main culprit in the pathogenesis of ischemia/reperfusion (I/R) injury. Suppression of oxidative stress is therefore critical in the treatment of I/R injury. Here, we report H2O2-activatable antioxidant prodrug (BRAP) that is capable of specifically targeting the site of oxidative stress and exerting anti-inflammatory and anti-apoptotic activities. BRAP with a self-immolative boronic ester protecting group was designed to scavenge H2O2 and release HBA (p-hydroxybenzyl alcohol) with antioxidant and anti-inflammatory activities. BRAP exerted potent antioxidant and anti-inflammatory activity in lipopolysaccharide (LPS)- and H2O2-stimulated cells by suppressing the generation of ROS and pro-inflammatory cytokines. In mouse models of hepatic I/R and cardiac I/R, BRAP exerted potent antioxidant, anti-inflammatory and anti-apoptotic activities due to the synergistic effects of H2O2-scavenging boronic esters and therapeutic HBA. In addition, administration of high doses of BRAP daily for 7 days showed no renal or hepatic function abnormalities. Therefore BRAP has tremendous therapeutic potential as H2O2-activatable antioxidant prodrug for the treatment of I/R injuries.
authors.affiliation: Department of BIN Convergence Technology, Chonbuk National University, Jeonju, Chonbuk 561-756, Republic of Korea.|Polymer Fusion Research Center, Department of Polymer·Nano Science and Technology, Chonbuk National University, Jeonju, Chonbuk 561-756, Republic of Korea.
authors.forename: Dongwon
authors.initials: D
authors.lastname: Lee
authors.affiliation: Department of BIN Convergence Technology, Chonbuk National University, Jeonju, Chonbuk 561-756, Republic of Korea.
authors.forename: Seunggyu
authors.initials: S
authors.lastname: Park
authors.affiliation: Cardiovascular Institute, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, United States.
authors.forename: Soochan
authors.initials: S
authors.lastname: Bae
authors.affiliation: Department of BIN Convergence Technology, Chonbuk National University, Jeonju, Chonbuk 561-756, Republic of Korea.
authors.forename: Dahee
authors.initials: D
authors.lastname: Jeong
authors.affiliation: Department of BIN Convergence Technology, Chonbuk National University, Jeonju, Chonbuk 561-756, Republic of Korea.
authors.forename: Minhyung
authors.initials: M
authors.lastname: Park
authors.affiliation: Department of BIN Convergence Technology, Chonbuk National University, Jeonju, Chonbuk 561-756, Republic of Korea.
authors.forename: Changsun
authors.initials: C
authors.lastname: Kang
authors.affiliation: Department of BIN Convergence Technology, Chonbuk National University, Jeonju, Chonbuk 561-756, Republic of Korea.
authors.forename: Wooyoung
authors.initials: W
authors.lastname: Yoo
authors.affiliation: Department of BIN Convergence Technology, Chonbuk National University, Jeonju, Chonbuk 561-756, Republic of Korea.|Cardiovascular Institute, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, United States.
authors.forename: Mohammed A
authors.initials: MA
authors.lastname: Samad
authors.affiliation: Cardiovascular Institute, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, United States.
authors.forename: Qingen
authors.initials: Q
authors.lastname: Ke
authors.affiliation: Department of BIN Convergence Technology, Chonbuk National University, Jeonju, Chonbuk 561-756, Republic of Korea.|Polymer Fusion Research Center, Department of Polymer·Nano Science and Technology, Chonbuk National University, Jeonju, Chonbuk 561-756, Republic of Korea.
authors.forename: Gilson
authors.initials: G
authors.lastname: Khang
authors.affiliation: Cardiovascular Institute, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, United States.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Kang
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D000975:Antioxidants / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001592:Benzyl Alcohols / Q000494:pharmacology; D001897:Boronic Acids / Q000737:chemistry / Q000494:pharmacology*; D053148:Caspase 3 / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D015870:Gene Expression / Q000187:drug effects; D006861:Hydrogen Peroxide / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015151:Immunoblotting; D008099:Liver / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008807:Mice, Inbred BALB C; D018613:Microscopy, Confocal; D015394:Molecular Structure; D015428:Myocardial Reperfusion Injury / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control; D011355:Prodrugs / Q000737:chemistry / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors / Q000378:metabolism; D015427:Reperfusion Injury / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D000975:Antioxidants; D001592:Benzyl Alcohols; D001897:Boronic Acids; D011355:Prodrugs; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; C018966:4-hydroxybenzyl alcohol; D006861:Hydrogen Peroxide; D053148:Caspase 3