Key Laboratory of Advanced Technologies of Materials, Ministry of Education, School of Materials Science and Engineering, Southwest Jiaotong University, Chengdu 610031, P. R. China.
J Mater Chem B. 2019 Mar 7;7(9):1415-1426. doi: 10.1039/c8tb02843e. Epub 2019 Feb 4.
The term synergism means that the overall therapeutic benefits should be greater than the sum of the effects of individual agents and that the optimal therapeutic efficacy can be achieved at reduced doses. Micellar systems usually fail to deliver multiple drugs to target sites at synergistic doses and thus are not able to maximize the antitumor efficacy. In the current study, we demonstrate a strategy to coordinate the release of camptothecin (CPT) and α-tocopheryl succinate (TOS) from hybrid micelles for nucleus and mitochondrion interferences. TOS is decorated with cationic triphenylphosphonium (TPP) to promote the targeting capability of TOS-TPP to mitochondria. The combination of CPT and TOS-TPP shows strong synergistism with a combination index of 0.186. Hyaluronic acid (HA) is conjugated with CPT or TOS-TPP via disulfide linkages for tumor cell targeting and intracellular reduction-triggered release. Both conjugates either separately self-assemble into M and M micelles, or are blended at different ratios to form M hybrid micelles. In response to elevated intracellular glutathione levels, the coordinated release of CPT and TOS-TPP from M results in a combination index of 0.26 and the dose-reduction indexes of CPT and TOS are 7.7 and 3.4, respectively. Compared with M and M, M micelles with 5 fold lower doses exhibit higher intracellular reactive oxygen species (ROS) levels, comparable tumor growth inhibition and animal survival, indicating no hematologic and intestinal toxicities. Moreover, the HA conjugates of M are linked to polylactide via acid-labile linkages and electrospun into short fibers (M@SF) as an injectable depot to release M in response to the acidic tumor microenvironment. At a predetermined synergistic ratio, M@SF with 5 fold lower doses achieves antitumor profiles comparable to those of individual micelle-loaded short fibers. Therefore, the hybrid micelles and micelle-releasing short fibers represent a feasible strategy to synergistically enhance the therapeutic efficacy and enable significant reduction in effective doses of chemotherapeutic agents.
协同作用是指整体治疗效果应该大于单个药物的效果之和，并且可以在降低剂量的情况下达到最佳的治疗效果。胶束系统通常无法以协同剂量将多种药物递送到靶部位，因此无法最大限度地提高抗肿瘤疗效。在本研究中，我们展示了一种从混合胶束中协调释放喜树碱（CPT）和α-生育酚琥珀酸酯（TOS）以干扰核和线粒体的策略。TOS 用阳离子三苯基膦（TPP）进行修饰，以提高 TOS-TPP 对线粒体的靶向能力。CPT 和 TOS-TPP 的组合具有很强的协同作用，组合指数为 0.186。透明质酸（HA）通过二硫键与 CPT 或 TOS-TPP 缀合，用于肿瘤细胞靶向和细胞内还原触发释放。两种缀合物分别自组装成 M 和 M 胶束，或按不同比例混合形成 M 混合胶束。响应细胞内谷胱甘肽水平的升高，M 中 CPT 和 TOS-TPP 的协同释放导致组合指数为 0.26，CPT 和 TOS 的剂量减少指数分别为 7.7 和 3.4。与 M 和 M 相比，M 胶束的剂量降低了 5 倍，表现出更高的细胞内活性氧（ROS）水平，相当的肿瘤生长抑制和动物存活率，表明没有血液学和肠道毒性。此外，M 的 HA 缀合物通过酸不稳定键与聚乳酸连接，并通过电纺成短纤维（M@SF）作为可注射储存库，以响应酸性肿瘤微环境释放 M。在预定的协同比例下，M@SF 的剂量降低了 5 倍，达到了与单个载药短纤维相当的抗肿瘤特征。因此，混合胶束和胶束释放短纤维代表了一种可行的策略，可以协同增强治疗效果，并显著降低化疗药物的有效剂量。
