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

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.

• Authors: 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
• Journal: Nanomedicine : nanotechnology, biology, and medicine (Nanomedicine) Vol. 29 Pg. 102266 (10 2020) ISSN: 1549-9642 [Electronic] United States
• PMID: 32679269 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 Elsevier Inc. All rights reserved.

Chemical References

• N(6)-(5-hydroxy-2-pyridyl)methyladenosine
• Polymers
• Prodrugs
• Dexamethasone
• Adenosine

Topics

• Adenosine (analogs & derivatives, chemistry, pharmacology)
• Animals
• Dexamethasone (chemistry, pharmacology)
• Disease Models, Animal
• Humans
• Kidney (drug effects)
• Lupus Nephritis (drug therapy, pathology)
• Mice
• Mice, Inbred NZB
• Nanomedicine
• Nanoparticles (chemistry)
• Polymers (chemistry, pharmacology)
• Prodrugs (chemistry, pharmacology)
• Spleen (drug effects)
• Tissue Distribution (drug effects)