Nanomicelle formulation modifies the pharmacokinetic profiles and cardiac toxicity of daunorubicin.
Nanomicelle formulation modifies the pharmacokinetic profiles and cardiac toxicity of daunorubicin.
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DOI：
10.2217/nnm.14.44
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发表时间：
2014
期刊：
影响因子：
--
通讯作者：
Pan CX
中科院分区：
文献类型：
--
作者：
Zhang H;Li Y;Lin TY;Xiao K;Haddad AS;Henderson PT;Jonas BA;Chen M;Xiao W;Liu R;Lam KS;Pan CX
柔红霉素（DNR）治疗急性髓系白血病的疗效中等，但有明显的副作用，包括心脏毒性。我们最近开发了一种纳米胶束配方的DNR，专门针对急性髓系白血病干细胞。在Balb/c小鼠和Sprague-Dawley大鼠体内进行游离DNR、DNR的药代动力学分析。采用组织化学染色、caspase 3/7、肌钙蛋白和肌酸激酶MB同工酶进行毒性评价。与游离DNR相比，纳米束状DNR的心脏毒性更小，注射后心肌组织caspase 3/7活性降低（p = 0.002），血浆肌酸激酶MB同功酶降低（p = 0.002），肌钙蛋白浓度降低（p = 0.001）。DNR胶束浓度下的曲线下面积在小鼠中增加了31.9倍（p < 0.0001），在大鼠中增加了22.0倍（p < 0.001）。靶向白血病干细胞的胶束显著改变了药代动力学，降低了DNR的心脏毒性，这可能使基于DNR的急性髓性白血病的治疗得到改善。
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. 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. 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). 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.