Department of Pharmaceutics, College of Pharmacy, University of Minnesota, 308 Harvard Street SE, Minneapolis, MN 55455, USA.
Stem Cell Institute and Veterinary Population Medicine Department, University of Minnesota, 1365 Gortner Avenue, Saint Paul, MN 55108, USA.
J Control Release. 2014 Dec 28;196:243-51. doi: 10.1016/j.jconrel.2014.10.015. Epub 2014 Oct 23.
Poor availability in deep-seated solid tumors is a significant challenge that limits the effectiveness of currently used anticancer drugs. Approaches that can specifically enhance drug delivery to the tumor tissue can potentially improve therapeutic efficacy. In our current studies, we used nano-engineered mesenchymal stem cells (nano-engineered MSCs) as tumor-targeted therapeutic carriers. In addition to their exquisite tumor homing capabilities, MSCs overexpress efflux transporters such as P-glycoprotein and are highly drug resistant. The inherent tumor-tropic and drug-resistant properties make MSCs ideal carriers for toxic payload. Nano-engineered MSCs were prepared by treating human MSCs with drug-loaded polymeric nanoparticles. Incorporating nanoparticles in MSCs did not affect their viability, differentiation or migration potential. Nano-engineered MSCs induced dose-dependent cytotoxicity in A549 lung adenocarcinoma cells and MA148 ovarian cancer cells in vitro. An orthotopic A549 lung tumor model was used to monitor the in vivo distribution of nanoengineered MSCs. Intravenous injection of nanoparticles resulted in non-specific biodistribution, with significant accumulation in the liver and spleen while nano-engineered MSCs demonstrated selective accumulation and retention in lung tumors. These studies demonstrate the feasibility of developing nano-engineered MSCs loaded with high concentration of anticancer agents without affecting their tumor-targeting or drug resistance properties.
深层实体肿瘤中药物的有效浓度低是一个重大挑战，限制了目前应用的抗癌药物的疗效。能够特异性提高药物向肿瘤组织传递的方法可能会提高治疗效果。在我们目前的研究中，我们使用了纳米工程间充质干细胞（nano-engineered MSCs）作为肿瘤靶向治疗载体。除了具有极好的肿瘤归巢能力外，间充质干细胞还过表达外排转运蛋白，如 P 糖蛋白，具有很强的耐药性。间充质干细胞固有的肿瘤趋向性和耐药性使其成为毒性有效载荷的理想载体。纳米工程间充质干细胞是通过用载药聚合物纳米颗粒处理人骨髓间充质干细胞制备的。将纳米颗粒纳入间充质干细胞不会影响其活力、分化或迁移潜能。纳米工程间充质干细胞在体外诱导 A549 肺腺癌细胞和 MA148 卵巢癌细胞产生剂量依赖性细胞毒性。使用原位 A549 肺肿瘤模型监测纳米工程间充质干细胞的体内分布。静脉注射纳米颗粒会导致非特异性生物分布，肝和脾中积累显著，而纳米工程间充质干细胞则在肺肿瘤中表现出选择性的积累和保留。这些研究表明，开发载有高浓度抗癌药物的纳米工程间充质干细胞是可行的，而不会影响其肿瘤靶向性或耐药性。
