Cooperation of IRAK1/4 inhibitor and ABT-737 in nanoparticles for synergistic therapy of T cell acute lymphoblastic leukemia.
Cooperation of IRAK1/4 inhibitor and ABT-737 in nanoparticles for synergistic therapy of T cell acute lymphoblastic leukemia.
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DOI：
10.2147/ijn.s146875
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发表时间：
2017
影响因子：
8
通讯作者：
Jin R
中科院分区：
文献类型：
--
作者：
Wu X;Wang L;Qiu Y;Zhang B;Hu Z;Jin R
T细胞急性淋巴细胞白血病(T-ALL)是由变异型T细胞前体细胞的克隆性扩增引起的，被认为是一种高危白血病。由于T-ALL的动态和多功能性，当代单一化疗的效果有限。本研究将IRAK1/4抑制剂和ABT-737共包裹到聚乙二醇化的聚乳酸-乙醇酸共聚纳米粒(IRAK/ABT-NP)中，以增强T-ALL的协同治疗。采用Box-Behnken设计和响应面方法对处方进行了优化，以实现高载药量。最佳工艺参数为：聚合物在乙腈中的质量分数为2.98%，油水比为1：8.33，乳化剂浓度为2.12%。载药量高，球形均匀。体外释放实验显示IRAK1/4抑制剂缓释72小时，ABT-737缓释120小时以上。IRAK/ABT-NP对IRAK/ABT-NP的摄取效率和诱导T-ALL的凋亡率明显高于IRAK1/4和ABT-737混合液。在Jurkat细胞中，IRAK/ABT-NP的IC50比游离药物组合低一倍。此外，我们进行了体内实验，与IRAK1/4和ABT-737联合使用的溶液相比，IRAK/ABT-NP对T-ALL细胞具有更强的细胞毒性，显著恢复外周血中的白细胞数量，并延长T-ALL小鼠模型的存活时间。
T cell acute lymphoblastic leukemia (T-ALL) is caused by clonal expansion of variant T cell progenitors and is considered as a high risk leukemia. Contemporary single chemotherapy has a limited effect due to dynamic and versatile properties of T-ALL. Here IRAK1/4 inhibitor and ABT-737 were co-encapsulated into polyethylene glycol modified poly (lactic-co-glycolic acid) nanoparticles (IRAK/ABT-NP) to enhance synergistic therapy of T-ALL. The formulation was optimized to achieve high drug loading using Box-Behnken design and response surface methodology. The optimal parameter comprised 2.98% polymer in acetonitrile, a ratio of oil phase to water phase of 1:8.33, and 2.12% emulsifier concentration. High drug loading and uniform spherical shape was achieved. In vitro release study showed sustained release of IRAK1/4 inhibitor for 72 hours as well as sustained release of ABT-737 for more than 120 hours. Uptake efficiency of IRAK/ABT-NP and induced apoptotic T-ALL fraction by IRAK/ABT-NP were much higher than the IRAK1/4 and ABT-737 combined solution. IC50 of IRAK/ABT-NP was two-fold lower than free drug combination in Jurkat cells. Additionally, we conducted in vivo experiments in which IRAK/ABT-NP exhibited greater cytotoxicity toward T-ALL cells, the capacity to significantly restore white blood cell number in peripheral blood, and improved survival time of T-ALL mouse model compared to the IRAK1/4 and ABT-737 combined solution.