Head-to-head comparative pharmacokinetic and biodistribution (PK/BD) study of two dexamethasone prodrug nanomedicines on lupus-prone NZB/WF1 mice

Xin Wei, Gang Zhao, Xiaobei Wang, Nagsen Gautam, Zhenshan Jia, Zhifeng Zhao, Dexuan Kong, Fan Zhang, Sushil Kumar, Yuanyuan Sun, Ningrong Chen, Xiaoyan Wang, Libin Yang, Rongguo Ren, Geoffrey M. Thiele, Tatiana K. Bronich, James R. O'Dell, Yazen Alnouti, Dong Wang

Research output: Contribution to journalArticle

Abstract

HPMA copolymer-based dexamethasone prodrug (P-Dex) and PEG-based dexamethasone prodrug (PEG-Dex, ZSJ-0228) were previously found to passively target the inflamed kidney and provide potent and sustained resolution of nephritis in NZB/WF1 lupus-prone mice. While both prodrug nanomedicines effectively ameliorate lupus nephritis, they have demonstrated distinctively different safety profiles. To explore the underlining mechanisms of these differences, we conducted a head-to-head comparative PK/BD study of P-Dex and PEG-Dex on NZB/WF1 mice. Overall, the systemic organ/tissue exposures to P-Dex and Dex released from P-Dex were found to be significantly higher than those of PEG-Dex. The high prodrug concentrations were sustained in kidney for only 24 h, which cannot explain their lasting therapeutic efficacy (>1 month). P-Dex showed sustained presence in liver, spleen and adrenal gland, while the presence of PEG-Dex in these organs was transient. This difference in PK/BD profiles may explain PEG-Dex’ superior safety than P-Dex.

Original languageEnglish (US)
Article number102266
JournalNanomedicine: Nanotechnology, Biology, and Medicine
Volume29
DOIs
StatePublished - Oct 2020

Keywords

  • Dexamethasone
  • Lupus nephritis
  • P-Dex
  • Pharmacokinetics and biodistribution
  • Prodrug nanomedicine
  • ZSJ-0228

ASJC Scopus subject areas

  • Bioengineering
  • Medicine (miscellaneous)
  • Molecular Medicine
  • Biomedical Engineering
  • Materials Science(all)
  • Pharmaceutical Science

Fingerprint Dive into the research topics of 'Head-to-head comparative pharmacokinetic and biodistribution (PK/BD) study of two dexamethasone prodrug nanomedicines on lupus-prone NZB/WF1 mice'. Together they form a unique fingerprint.

  • Cite this