Department of Bioengineering, University of Washington, Seattle, WA 98195-5061, USA.
Biomaterials. 2010 Oct;31(28):7386-97. doi: 10.1016/j.biomaterials.2010.06.004. Epub 2010 Jul 3.
Doxorubicin (DOX) is an effective chemotherapeutic against a wide range of solid tumors. However, its clinical use is limited by severe side effects such as cardiotoxicity as well as inherent and acquired drug resistance of tumors. DOX encapsulation within self-assembled polymeric micelles has the potential to decrease the systemic distribution of free drug and enhance the drug accumulation in the tumor via the enhanced permeability and retention (EPR). In this study, DOX was encapsulated in micelles composed of poly (ethylene oxide)-poly [(R)-3-hydroxybutyrate]-poly (ethylene oxide) (PEO-PHB-PEO) triblock copolymers. Micelle size, DOX loading and DOX release were characterized. To evaluate DOX activity, micelles were tested in both monolayer cell cultures and three-dimensional (3-D) multicellular spheroids (MCS) that mimic solid tumors. Antitumor activity in vivo was further studied with tumor-bearing mice. The micelles improved the efficiency of Dox penetration in 3-D MCS compared with free DOX. Efficient cell killing by Dox-micelles in both monolayer cells and 3-D MCS was also demonstrated. Finally, DOX-loaded micelles mediate efficient tumor delivery from tail vein injections to tumor-bearing mice with much less toxicity compared with free DOX.
多柔比星（DOX）是一种广泛用于治疗各种实体瘤的有效化疗药物。然而，其临床应用受到严重副作用（如心脏毒性）以及肿瘤固有的和获得性耐药性的限制。将 DOX 封装在自组装聚合物胶束内，有可能减少游离药物的全身分布，并通过增强通透性和滞留（EPR）作用增强药物在肿瘤中的积累。在这项研究中，DOX 被封装在由聚（乙二醇）-聚[（R）-3-羟基丁酸]-聚（乙二醇）（PEO-PHB-PEO）三嵌段共聚物组成的胶束中。对胶束的粒径、DOX 载药量和 DOX 释放进行了表征。为了评估 DOX 的活性，将胶束分别在单层细胞培养物和模拟实体瘤的三维（3-D）多细胞球体（MCS）中进行了测试。还通过荷瘤小鼠进一步研究了体内的抗肿瘤活性。与游离 DOX 相比，胶束提高了 DOX 在 3-D MCS 中的渗透效率。在单层细胞和 3-D MCS 中，Dox-胶束也表现出了高效的细胞杀伤作用。最后，与游离 DOX 相比，载 DOX 的胶束通过尾静脉注射对荷瘤小鼠具有更有效的肿瘤传递作用，且毒性更小。
