4-Amino-6-hydroxypyrazolo [3,4-d]pyrimidine (AHPP) conjugated PEG micelles: Water soluble polymeric xanthine oxidase inhibitor

Gahininath Y. Bharate, Jun Fang, Hideaki Nakamura, Haibo Qin, Seiji Shinkai, Hiroshi Maeda

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4 Citations (Scopus)


Xanthine oxidase (XO) is the major source of superoxide anion (O2 -) that is associated with various reactive oxygen species (ROS) related diseases. 4-amino-6-hydroxypyrazolo[3,4-d]pyrimidine (AHPP) is a potent XO inhibitor discovered in Maeda's laboratory, which is now being developed for the treatment of ischemia reperfusion injury and inflammatory diseases. However, the poor aqueous solubility of AHPP at physiological pH hampers its clinical development. To overcome this drawback, in the present study water soluble polyethyleneglycol conjugated AHPP (AHPP-PEG) was synthesized via two different approaches, which resulted in two derivatives of AHPP-PEG, namely, mono-AHPP-PEG and bis-(AHPP)-PEG depending on the number of AHPP on PEG chain. We characterized both conjugates by UV, FTIR spectroscopy and elemental analysis. Dynamic light scattering and Sephadex G-100 chromatography studies revealed mean particle size of 164.1 and 218.8nm and Mw. equivalent to 107 and 126kDa for mono-AHPP-PEG and bis-(AHPP)-PEG, respectively. Further, XO inhibitory activity for mono-AHPP-PEG and bis-(AHPP)-PEG were found with Ki of 0.23±0.03 and 0.21±0.03 M, respectively. In vivo pharmacokinetic study showed longer circulation time of AHPP-PEG conjugates compared to free AHPP. These results indicate AHPP-PEG conjugates have better potentials with supramolecular assemblies in aqueous medium and may become a good candidate for the treatment of ROS related diseases.

Original languageEnglish
Pages (from-to)954-966
Number of pages13
JournalJournal of Drug Targeting
Issue number10
Publication statusPublished - Dec 2011
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Pharmaceutical Science


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