Department of Pharmaceutical Sciences, College of Medicine, University of Nebraska Medical Center, Omaha, NE, USA.
Department of Pharmacy Practice and Science, College of Pharmacy, College of Medicine, University of Nebraska Medical Center, Omaha, NE, USA.
Nanomedicine. 2020 Oct;29:102266. doi: 10.1016/j.nano.2020.102266. Epub 2020 Jul 15.
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 HPMA 共聚物载倍他米松前药（P-Dex）和 PEG 载倍他米松前药（PEG-Dex，ZSJ-0228）能够被动靶向炎症肾脏，并为 NZB/WF1 狼疮易感小鼠提供有效的、持续的肾炎缓解作用。虽然这两种前药纳米药物都能有效改善狼疮肾炎，但它们表现出明显不同的安全性特征。为了探究这些差异的潜在机制，我们在 NZB/WF1 小鼠中进行了 P-Dex 和 PEG-Dex 的头对头比较 PK/BD 研究。总体而言，P-Dex 及其释放的倍他米松在全身器官/组织中的暴露量明显高于 PEG-Dex。这种高前药浓度仅在肾脏中持续 24 小时，这不能解释它们持久的治疗效果（>1 个月）。P-Dex 在肝脏、脾脏和肾上腺中持续存在，而 PEG-Dex 在这些器官中的存在是短暂的。这种 PK/BD 特征的差异可能解释了 PEG-Dex 比 P-Dex 具有更好的安全性。
