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

doi:10.1016/j.nano.2020.102266

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 journal › Article › peer-review

9 Scopus citations

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 language	English (US)
Article number	102266
Journal	Nanomedicine: Nanotechnology, Biology, and Medicine
Volume	29
DOIs	https://doi.org/10.1016/j.nano.2020.102266
State	Published - 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
General Materials Science
Pharmaceutical Science

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10.1016/j.nano.2020.102266

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Wei, X., Zhao, G., Wang, X., Gautam, N., Jia, Z., Zhao, Z., Kong, D., Zhang, F., Kumar, S., Sun, Y., Chen, N., Wang, X., Yang, L., Ren, R., Thiele, G. M., Bronich, T. K., O'Dell, J. R., Alnouti, Y., & Wang, D. (2020). Head-to-head comparative pharmacokinetic and biodistribution (PK/BD) study of two dexamethasone prodrug nanomedicines on lupus-prone NZB/WF1 mice. Nanomedicine: Nanotechnology, Biology, and Medicine, 29, Article 102266. https://doi.org/10.1016/j.nano.2020.102266

Wei, X, Zhao, G, Wang, X, Gautam, N, Jia, Z, Zhao, Z, Kong, D, Zhang, F, Kumar, S, Sun, Y, Chen, N, Wang, X, Yang, L, Ren, R, Thiele, GM, Bronich, TK, O'Dell, JR , Alnouti, Y & Wang, D 2020, 'Head-to-head comparative pharmacokinetic and biodistribution (PK/BD) study of two dexamethasone prodrug nanomedicines on lupus-prone NZB/WF1 mice', Nanomedicine: Nanotechnology, Biology, and Medicine, vol. 29, 102266. https://doi.org/10.1016/j.nano.2020.102266

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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{\textquoteright} superior safety than P-Dex.",

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

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year = "2020",

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doi = "10.1016/j.nano.2020.102266",

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AU - Wei, Xin

AU - Zhao, Gang

AU - Wang, Xiaobei

AU - Gautam, Nagsen

AU - Jia, Zhenshan

AU - Zhao, Zhifeng

AU - Kong, Dexuan

AU - Zhang, Fan

AU - Kumar, Sushil

AU - Sun, Yuanyuan

AU - Chen, Ningrong

AU - Wang, Xiaoyan

AU - Yang, Libin

AU - Ren, Rongguo

AU - Thiele, Geoffrey M.

AU - Bronich, Tatiana K.

AU - O'Dell, James R.

AU - Alnouti, Yazen

AU - Wang, Dong

PY - 2020/10

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N2 - 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.

AB - 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.

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

Abstract

Keywords

ASJC Scopus subject areas

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