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.

先前发现基于 HPMA 共聚物的地塞米松前药 (P-Dex) 和基于 PEG 的地塞米松前药 (PEG-Dex, ZSJ-0228) 被动靶向发炎的肾脏并提供有效和持续的解决 NZB/WF1 狼疮倾向的肾炎老鼠。虽然这两种前药纳米药物都能有效改善狼疮性肾炎，但它们的安全性却截然不同。为了探索这些差异的重要机制，我们对 NZB/WF1 小鼠进行了 P-Dex 和 PEG-Dex 的头对头比较 PK/BD 研究。总体而言，发现全身器官/组织暴露于 P-Dex 和从 P-Dex 释放的 Dex 显着高于 PEG-Dex。高前药浓度在肾脏中仅持续 24 小时，这不能解释其持久的治疗效果（> 1 个月）。P-Dex 在肝脏、脾脏和肾上腺中持续存在，而在这些器官中 PEG-Dex 的存在是短暂的。PK/BD 曲线的这种差异可以解释 PEG-Dex 比 P-Dex 优越的安全性。