Paclitaxel nanoparticle awakens immune system to fight against cancer
Paclitaxel nanoparticle awakens immune system to fight against cancer
复制标题
紫杉醇纳米粒子唤醒免疫系统对抗癌症
DOI：
10.1039/c6nr09895a
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发表时间：
2017
期刊：
影响因子：
6.7
通讯作者：
Liang Gaolin
中科院分区：
文献类型：
--
作者：
Tang Wei;Yang Jingbo;Yuan Yue;Zhao Zhibin;Lian Zhexiong;Liang Gaolin
高浓度的紫杉醇(PTX)用于抗肿瘤化疗，但对免疫细胞有毒性。在较低浓度下，PTX被发现能够刺激免疫细胞的抗肿瘤能力。因此，在维持其对免疫细胞的抗肿瘤刺激作用的同时，降低高浓度的PTX的细胞毒性仍然具有挑战性。在此，我们通过点击缩合反应，合理地设计了PTX衍生物Cys(StBu)-Arg-Lys(PTX)-CBT(1)，以方便地制备其纳米粒子1-NP。体外实验表明，在较高的PTX浓度下，1-NP对巨噬细胞的细胞毒性明显低于PTX，并能有效地被巨噬细胞吞噬，从而以剂量依赖的方式使细胞极化到抗肿瘤状态。体内实验进一步证实，1-NP具有比游离PTX更高的抗肿瘤效果，但对免疫器官和肿瘤部位的免疫细胞的细胞毒作用更低。我们的结果提示，通过使用不同剂量的1-NP，患者可以精确地调节免疫系统的激活，从而有效地抗肿瘤和平衡自身免疫反应。我们还设想，我们的战略可能导致免疫疗法和化疗的结合使用，以在未来获得更有效的抗肿瘤治疗。
A high concentration of paclitaxel (PTX) is used as an anti-tumor chemotherapy but is toxic to immune cells. At lower concentrations, PTX was found able to stimulate the anti-tumor potentials of immune cells. Thus, decreasing the cytotoxicity of PTX at high concentration while maintaining its anti-tumor stimulation to immune cells remains challenging. Herein, by employing a click condensation reaction, we rationally designed a PTX derivative, Cys(StBu)-Arg-Arg-Arg-Lys(PTX)-CBT (1), for the facile preparation of its nanoparticle 1-NP. In vitro assays indicated that, at high PTX concentrations, 1-NP showed significantly lower cytotoxicity to macrophages than did PTX, and could be efficiently phagocytosed by macrophages and consequently polarize the cells into an anti-tumor state in a dose-dependent manner. In vivo experiments further confirmed that 1-NP had a higher anti-tumor efficacy than did free PTX but lower cytotoxicity to immune cells in both immune organs and tumor sites. Our results suggest that, by using different doses of 1-NP, patients can precisely regulate the activation of the immune system for an effective anti-tumor and balanced autoimmune responses. We also envision that our strategy could lead to a combined use of immunotherapy and chemotherapy for a more efficient anti-tumor treatment in the future.