Nanomicelle formulation modifies the pharmacokinetic profiles and cardiac toxicity of daunorubicin

Hongyong Zhang; Yuanpei Li; Tzu Yin Lin; Kai Xiao; Ashraf S. Haddad; Paul T. Henderson; Brian A. Jonas; Mingyi Chen; Wenwu Xiao; Ruiwu Liu; Kit S. Lam; Chong Xian Pan

doi:10.2217/NNM.14.44

Nanomicelle formulation modifies the pharmacokinetic profiles and cardiac toxicity of daunorubicin

Hongyong Zhang, Yuanpei Li, Tzu Yin Lin, Kai Xiao, Ashraf S. Haddad, Paul T. Henderson, Brian A. Jonas, Mingyi Chen, Wenwu Xiao, Ruiwu Liu, Kit S. Lam, Chong Xian Pan

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9 Scopus citations

Abstract

Background: Treatment with daunorubicin (DNR) in acute myeloid leukemia is moderately effective and associated with significant side effects, including cardiac toxicity. We recently developed a nanomicellar formulation of DNR that specifically targets acute myeloid leukemia stem cells. Materials & methods: Pharmacokinetics analysis of free DNR, DNR in nanomicellar formulations was performed in Balb/c mice and Sprague - Dawley rats. Histochemical staining, caspase 3/7, troponin and creatine kinase MB isoenzyme were used to assess toxicity. Results: Compared with free DNR, the nanomicellar formulations of DNR had less cardiotoxicity as evidenced by milder histopathological changes, lower caspase 3/7 activity in heart tissue (p = 0.002), lower plasma creatine kinase MB isoenzyme (p = 0.002) and troponin concentrations (p = 0.001) postinjection. The area under curve concentration of DNR in micelles increased by 31.9-fold in mice (p < 0.0001) and 22.0-fold higher in rats (p < 0.001). Conclusion: Leukemia stem cell-targeting micelles dramatically change the pharmacokinetics and reduce the cardiac toxicity of DNR, which may enable improved DNR-based treatment of acute myeloid leukemia.

Original language	English (US)
Pages (from-to)	1807-1820
Number of pages	14
Journal	Nanomedicine
Volume	9
Issue number	12
DOIs	https://doi.org/10.2217/NNM.14.44
State	Published - Aug 1 2014

Keywords

Cardiotoxicity
Daunorubicin
Leukemia stem cells
Nanomicelles
Pharmacokinetics

ASJC Scopus subject areas

Bioengineering
Medicine (miscellaneous)
Biomedical Engineering
Materials Science(all)

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10.2217/NNM.14.44

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title = "Nanomicelle formulation modifies the pharmacokinetic profiles and cardiac toxicity of daunorubicin",

abstract = "Background: Treatment with daunorubicin (DNR) in acute myeloid leukemia is moderately effective and associated with significant side effects, including cardiac toxicity. We recently developed a nanomicellar formulation of DNR that specifically targets acute myeloid leukemia stem cells. Materials & methods: Pharmacokinetics analysis of free DNR, DNR in nanomicellar formulations was performed in Balb/c mice and Sprague - Dawley rats. Histochemical staining, caspase 3/7, troponin and creatine kinase MB isoenzyme were used to assess toxicity. Results: Compared with free DNR, the nanomicellar formulations of DNR had less cardiotoxicity as evidenced by milder histopathological changes, lower caspase 3/7 activity in heart tissue (p = 0.002), lower plasma creatine kinase MB isoenzyme (p = 0.002) and troponin concentrations (p = 0.001) postinjection. The area under curve concentration of DNR in micelles increased by 31.9-fold in mice (p < 0.0001) and 22.0-fold higher in rats (p < 0.001). Conclusion: Leukemia stem cell-targeting micelles dramatically change the pharmacokinetics and reduce the cardiac toxicity of DNR, which may enable improved DNR-based treatment of acute myeloid leukemia.",

keywords = "Cardiotoxicity, Daunorubicin, Leukemia stem cells, Nanomicelles, Pharmacokinetics",

author = "Hongyong Zhang and Yuanpei Li and Lin, {Tzu Yin} and Kai Xiao and Haddad, {Ashraf S.} and Henderson, {Paul T.} and Jonas, {Brian A.} and Mingyi Chen and Wenwu Xiao and Ruiwu Liu and Lam, {Kit S.} and Pan, {Chong Xian}",

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doi = "10.2217/NNM.14.44",

language = "English (US)",

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T1 - Nanomicelle formulation modifies the pharmacokinetic profiles and cardiac toxicity of daunorubicin

AU - Zhang, Hongyong

AU - Li, Yuanpei

AU - Lin, Tzu Yin

AU - Xiao, Kai

AU - Haddad, Ashraf S.

AU - Henderson, Paul T.

AU - Jonas, Brian A.

AU - Chen, Mingyi

AU - Xiao, Wenwu

AU - Liu, Ruiwu

AU - Lam, Kit S.

AU - Pan, Chong Xian

PY - 2014/8/1

Y1 - 2014/8/1

N2 - Background: Treatment with daunorubicin (DNR) in acute myeloid leukemia is moderately effective and associated with significant side effects, including cardiac toxicity. We recently developed a nanomicellar formulation of DNR that specifically targets acute myeloid leukemia stem cells. Materials & methods: Pharmacokinetics analysis of free DNR, DNR in nanomicellar formulations was performed in Balb/c mice and Sprague - Dawley rats. Histochemical staining, caspase 3/7, troponin and creatine kinase MB isoenzyme were used to assess toxicity. Results: Compared with free DNR, the nanomicellar formulations of DNR had less cardiotoxicity as evidenced by milder histopathological changes, lower caspase 3/7 activity in heart tissue (p = 0.002), lower plasma creatine kinase MB isoenzyme (p = 0.002) and troponin concentrations (p = 0.001) postinjection. The area under curve concentration of DNR in micelles increased by 31.9-fold in mice (p < 0.0001) and 22.0-fold higher in rats (p < 0.001). Conclusion: Leukemia stem cell-targeting micelles dramatically change the pharmacokinetics and reduce the cardiac toxicity of DNR, which may enable improved DNR-based treatment of acute myeloid leukemia.

AB - Background: Treatment with daunorubicin (DNR) in acute myeloid leukemia is moderately effective and associated with significant side effects, including cardiac toxicity. We recently developed a nanomicellar formulation of DNR that specifically targets acute myeloid leukemia stem cells. Materials & methods: Pharmacokinetics analysis of free DNR, DNR in nanomicellar formulations was performed in Balb/c mice and Sprague - Dawley rats. Histochemical staining, caspase 3/7, troponin and creatine kinase MB isoenzyme were used to assess toxicity. Results: Compared with free DNR, the nanomicellar formulations of DNR had less cardiotoxicity as evidenced by milder histopathological changes, lower caspase 3/7 activity in heart tissue (p = 0.002), lower plasma creatine kinase MB isoenzyme (p = 0.002) and troponin concentrations (p = 0.001) postinjection. The area under curve concentration of DNR in micelles increased by 31.9-fold in mice (p < 0.0001) and 22.0-fold higher in rats (p < 0.001). Conclusion: Leukemia stem cell-targeting micelles dramatically change the pharmacokinetics and reduce the cardiac toxicity of DNR, which may enable improved DNR-based treatment of acute myeloid leukemia.

KW - Cardiotoxicity

KW - Daunorubicin

KW - Leukemia stem cells

KW - Nanomicelles

KW - Pharmacokinetics

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Nanomicelle formulation modifies the pharmacokinetic profiles and cardiac toxicity of daunorubicin

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