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/W F1 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/W F1 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 hours, which cannot explain their lasting therapeutic efficacy (> 1 month). P-*

Glucocorticoids-based prodrug design: Current strategies and research progress

“… [55] P-Dex PHPMA (41.8 kDa) Acid-activated Hydrazone Intravenous injection To treat Lupus Nephritis; Monthly administration reduces proteinuria and mortality in mice with LN without osteoporosis. [58] P-Dex PHPMA (37.1 kDa) Acid-activated Hydrazone Intravenous injection To treat murine calvaria osteolysis; Sustained retention for 6 d in disease sites; Excellent osteoprotective effects. [60] P-Dex PHPMA (36.8 kDa) Acid-activated Hydrazone Intravenous injection To treat murine osteolysis; Comparable therapeutic effect; Reduced systemic toxicity.…”

“…In addition to being used to treat rheumatoid arthritis [ 47 , [51] , [52] , [53] , [54] , 56 ], HPMA-Dex has also been widely extended to other diseases, such as LN [57] , [58] , [59] , inflammation caused by implants [60] , [61] , [62] , inflammatory bowel disease [63] , and tumors [64] . Among them, Wang's team not only studied the therapeutic effect of HMPA-Dex conjugates in the murine prosthesis failure model but also explored the influence of the molecular weight of prodrugs on both the therapeutic effect and the biodistribution in the body.…”

Macromolecular Dexamethasone Prodrug Ameliorates Neuroinflammation and Prevents Bone Loss Associated with Traumatic Brain Injury

“…Dexamethasone (Dex) is prescribed for the treatment of TBIassociated cerebral edema and inflammations. 18,19 Its ubiq- hydroxypropyl)methacrylamide (HPMA) copolymer-based dexamethasone (Dex) prodrug (P-Dex), which alters the Dex PK/BD and provides potent anti-inflammatory benefits in the treatment of inflammatory arthritis 20,21 and lupus nephritis, 22,25,26 with greatly reduced glucocorticoid side effects. Therefore, we envisioned that the use of P-Dex might also effectively ameliorate the TBI-induced neuroinflammation and associated symptoms.…”

“…To address these clinical challenges, we proposed the utility of an N -(2-hydroxypropyl)­methacrylamide (HPMA) copolymer-based dexamethasone (Dex) prodrug (P-Dex) for the treatment of TBI. The efficacy and safety of P-Dex have been extensively evaluated in many inflammatory and autoimmune disease animal models. − According to the ELVIS mechanism, P-Dex can passively target inflammation through the leaky vasculature associated with the pathologies. − Given the compromised blood–brain barrier (BBB) and brain inflammation in the secondary injury phase of the TBI patients, we hypothesized that the systemically administrated P-Dex will passively target the brain trauma injury sites, substantially enhance the GC therapy efficacy, and improve its safety. The experiments presented in this manuscript are intended to test this hypothesis.…”