Daunorubicin-containing CLL1-targeting nanomicelles have anti-leukemia stem cell activity in acute myeloid leukemia.
Daunorubicin-containing CLL1-targeting nanomicelles have anti-leukemia stem cell activity in acute myeloid leukemia.
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DOI：
10.1016/j.nano.2019.04.007
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发表时间：
2019-08
期刊：
影响因子：
--
通讯作者：
Jonas BA
中科院分区：
文献类型：
--
作者：
Lin TY;Zhu Y;Li Y;Zhang H;Ma AH;Long Q;Keck J;Lam KS;Pan CX;Jonas BA
急性髓系白血病患者预后非常差，与复发率高和药物相关毒性有关。白血病干细胞（LSCs）在化疗中存活的能力是复发的主要原因，消除LSCs是治愈的最终必要条件。我们开发了一种新的二硫交联cll1靶向胶束（DC-CTM），它可以将高浓度的柔红霉素（DNR）递送到大块白血病细胞和LSCs中。与游离DNR相比，DC-CTM-DNR的半衰期更长，曲线浓度下的DNR面积增加了11倍，并表现出优越的毒性特征。在患者源性AML异种移植模型中，与对照组相比，DC-CTM-DNR治疗导致AML移植和二次移植损伤显著减少。总的来说，我们证明了与游离DNR相比，DC-CTM-DNR具有优越的抗lsc /AML功效，并且具有更好的药代动力学和毒性谱。DC-CTM-DNR有可能显著改善AML患者的治疗结果，降低治疗相关的发病率和死亡率。白血病干细胞（Leukemia stem cells， LSC）可在化疗后复发的白血病中重新填充。CLL1仅在LSC上表达，而在造血干细胞上不表达，因此我们开发了CLL1靶向胶束，以提供高剂量的化疗细胞来根除LSC和大块白血病。这一策略从根本上治愈了白血病。
Patients with acute myeloid leukemia have a very poor prognosis related to a high rate of relapse and drug-related toxicity. The ability of leukemia stem cells (LSCs) to survive chemotherapy is primarily responsible for relapse, and eliminating LSCs is ultimately essential for cure. We developed novel disulfide-crosslinked CLL1-targeting micelles (DC-CTM), which can deliver high concentrations of daunorubicin (DNR) into both bulk leukemia cells and LSCs. Compared to free DNR, DC-CTM-DNR had a longer half-life, increased DNR area under the curve concentration by 11-fold, and exhibited a superior toxicity profile. In patient-derived AML xenograft models, DC-CTM-DNR treatment led to significant decreases in AML engraftment and impairment of secondary transplantation compared to control groups. Collectively, we demonstrate superior anti-LSC/AML efficacy, and preferable pharmacokinetic and toxicity profiles of DC-CTM-DNR compared to free DNR. DC-CTM-DNR has the potential to significantly improve treatment outcomes and reduce therapy-related morbidity and mortality for patients with AML. Leukemia stem cells (LSC) could repopulate the leukemia after chemotherapy resulting recurrence. CLL1 only expressed on LSC but not hematopoietic stem cells, and thus we developed CLL1 targeting micelles to deliver high dose of chemotherapeutic cells to eradicate LSC and bulk leukemia. This strategy cure leukemia from the root.
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影响因子：
50.5
作者：
O'Brien, MER;Wigler, N;Tendler, C
通讯作者：
Tendler, C
影响因子：
7.5
作者：
Jiang, Ying-Ping;Liu, Bob Y.;Junutula, Jagath R.
通讯作者：
Junutula, Jagath R.
DOI：
10.1016/j.nano.2011.12.004
发表时间：
2012-10-01
影响因子：
5.4
作者：
Zhang, Hongyong;Luo, Juntao;Pan, Chong-xian
通讯作者：
Pan, Chong-xian
DOI：
10.2217/nnm.14.44
发表时间：
2014
期刊：
Nanomedicine (London, England)
影响因子：
--
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
通讯作者：
Pan CX
影响因子：
20.3
作者：
van Rhenen, Anna;van Dongen, Guus A. M. S.;Schuurhuis, Gerrit Jan
通讯作者：
Schuurhuis, Gerrit Jan