Nanomicelle formulation modifies the pharmacokinetic profiles and cardiac toxicity of daunorubicin.

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Publication Year:
2014
Authors:
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
PubMed ID:
24628688
Funding Grants:
Public Summary:
Daunorubicin formulated in nanometer-scale micelles has favorable drug distribution in patients, signficantly reduced toxicity to heart and improved anti-tumor activity.
Scientific 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 submitted 24 January 2014; Revised submitted 28 February 2014.