Nano-Engineered Mesenchymal Stem Cells Increase Therapeutic Efficacy of Anticancer Drug Through True Active Tumor Targeting.
Nano-Engineered Mesenchymal Stem Cells Increase Therapeutic Efficacy of Anticancer Drug Through True Active Tumor Targeting.
复制标题
DOI：
10.1158/1535-7163.mct-17-0682
复制
发表时间：
2018-06
影响因子：
5.7
通讯作者：
Prabha S
中科院分区：
文献类型：
--
作者：
Layek B;Sadhukha T;Panyam J;Prabha S
肿瘤靶向给药具有提高抗癌药物疗效和减轻其非特异性毒性的潜力。然而，目前的药物递送方法依赖于药物载体在肿瘤中的低效被动积累。我们已经开发出一种独特的，真正有效的肿瘤靶向策略，该策略依赖于用载药纳米颗粒工程化间充质干细胞（MSC）。我们使用A549原位肺肿瘤模型的研究表明，携带抗癌药物紫杉醇（PTX）的纳米工程MSC可以回到肿瘤中，并产生细胞药物库，在几天内释放药物有效负载。尽管PTX的剂量显著较低，但纳米工程MSC导致肿瘤生长的显著抑制和上级存活。纳米工程化MSC的抗癌功效在具有原位刘易斯肺癌（LL/2-luc）肿瘤的免疫活性C57 BL/6白化病雌性小鼠中得到证实。此外，在产生等效治疗功效的剂量下，纳米工程化MSC对白色血细胞计数没有影响，而PTX溶液和PTX纳米颗粒治疗引起白细胞减少症。生物分布研究表明，在靶肺肿瘤中，纳米工程化MSC导致PTX的AUClung（1.5 µ g.天/g）比PTX溶液和纳米颗粒（分别为0.2和0.1 µ g.天/g组织）高9倍以上。此外，相对于PTX溶液和纳米颗粒组，纳米工程化MSC的PTX的肺-肝和肺-脾比率高出数倍，表明纳米工程化MSC表现出显著更少的脱靶沉积。总之，我们的研究结果表明，纳米工程MSC可以作为一种有效的载体，用于肿瘤特异性药物递送和显着提高传统化疗药物的抗癌疗效。
Tumor-targeted drug delivery has the potential to improve therapeutic efficacy and mitigate non-specific toxicity of anticancer drugs. However, current drug delivery approaches rely on inefficient passive accumulation of the drug carrier in the tumor. We have developed a unique, truly active tumor targeting strategy that relies on engineering mesenchymal stem cells (MSCs) with drug-loaded nanoparticles. Our studies using the A549 orthotopic lung tumor model show that nano-engineered MSCs carrying the anticancer drug paclitaxel (PTX) home to tumors and create cellular drug depots that release the drug payload over several days. Despite significantly lower doses of PTX, nano-engineered MSCs resulted in significant inhibition of tumor growth and superior survival. Anticancer efficacy of nano-engineered MSCs was confirmed in immunocompetent C57BL/6 albino female mice bearing orthotopic Lewis Lung Carcinoma (LL/2-luc) tumors. Further, at doses that resulted in equivalent therapeutic efficacy, nano-engineered MSCs had no effect on white blood cell count whereas PTX solution and PTX nanoparticle treatments caused leukopenia. Biodistribution studies showed that nano–engineered MSCs resulted in greater than 9–fold higher AUClung of PTX (1.5 µg.day/g) than PTX solution and nanoparticles (0.2 and 0.1 µg.day/g tissue, respectively) in the target lung tumors. Furthermore, the lung-to-liver and the lung-to-spleen ratios of PTX were several folds higher for nano-engineered MSCs relative to those for PTX solution and nanoparticle groups, suggesting that nano–engineered MSCs demonstrate significantly less off-target deposition. In summary, our results demonstrate that nano-engineered MSCs can serve as an efficient carrier for tumor specific drug delivery and significantly improved anti–cancer efficacy of conventional chemotherapeutic drugs.