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Water soluble PEG-conjugate of xanthine oxidase inhibitor, PEG-AHPP micelles, as a novel therapeutic for ROS related inflammatory bowel diseases
- Source :
- Journal of controlled release : official journal of the Controlled Release Society. 223
- Publication Year :
- 2015
-
Abstract
- Xanthine oxidase (XO) is one of the major enzymes to generate superoxide anion (O2(-)), that is frequently associated with various diseases involving reactive oxygen species (ROS). 4-Amino-6-hydroxypyrazolo[3,4-d]pyrimidine (AHPP) is a potent XO inhibitor showing therapeutic potential for oxidative inflammatory diseases. However its very poor aqueous solubility makes pharmaceutical application difficult. To overcome this drawback, we have successfully synthesized a water soluble polyethylene glycol (PEG) conjugate of AHPP (PEG-AHPP) that exhibited good water solubility, forming micelles in aqueous solution. In the present study, the in vivo pharmacokinetics of this PEG-AHPP was examined. Further its therapeutic potential was investigated in dextran sulfate sodium (DSS) induced mouse colitis model. Compared to parental AHPP, the plasma t1/2 of PEG-AHPP was increased remarkably from 3h to 14h, indicating macromolecular nature of AHPP in circulation. In the DSS induced colitis model, oral administration of 2% DSS in drinking water resulted in the progression of the colitis with diarrhea and hematochezia as well as shortening of the large bowel. Administration of PEG-AHPP intravenously (10mg/kg) or orally (20mg/kg) suppressed pathogenesis significantly; namely diarrhea was reduced markedly, and the length of large bowel returned to almost normal level. Pathological examination clearly revealed improvement of colonic ulcer or necrosis. Production of inflammatory cytokines, i.e., interleukin-6 and tumor necrosis factor (TNF)-α, was significantly increased in DSS-induced colitis mice. However, it was markedly suppressed by PEG-AHPP administration. Similar results were found when serum 8-hydroxydeoxyguanosine (8-OHdG) and thiobarbituric acid reactive substances (TBARS), that are the index of oxidative injury, were measured. PEG-AHPP thus may be a potential candidate drug for ROS-related diseases including inflammatory bowel disease.
- Subjects :
- 0301 basic medicine
Xanthine Oxidase
medicine.drug_class
Colon
Pharmaceutical Science
Oxypurinol
Pharmacology
Inflammatory bowel disease
Thiobarbituric Acid Reactive Substances
Proinflammatory cytokine
Polyethylene Glycols
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Oral administration
medicine
TBARS
Animals
Humans
Colitis
Xanthine oxidase
Xanthine oxidase inhibitor
Micelles
Mice, Inbred ICR
business.industry
Superoxide
Dextran Sulfate
Deoxyguanosine
Water
medicine.disease
030104 developmental biology
chemistry
Solubility
8-Hydroxy-2'-Deoxyguanosine
030220 oncology & carcinogenesis
Cytokines
Female
Caco-2 Cells
business
Reactive Oxygen Species
Subjects
Details
- ISSN :
- 18734995
- Volume :
- 223
- Database :
- OpenAIRE
- Journal :
- Journal of controlled release : official journal of the Controlled Release Society
- Accession number :
- edsair.doi.dedup.....d06e119c94ffbcc9851aa460cedb1611