Department of Pharmaceutical Sciences, Irma Lerma Rangel College of Pharmacy, Texas A&M University Health Science Center , Kingsville, Texas 78363, United States.
Department of Biomedical Engineering, School of Engineering & Applied Science, Yale University , New Haven, Connecticut 06511, United States.
ACS Appl Mater Interfaces. 2017 Nov 22;9(46):39971-39984. doi: 10.1021/acsami.7b11219. Epub 2017 Nov 7.
Because of the complexity of cancer, an ideal anticancer strategy is better to target both cancer cells and the tumor microenvironment. In this study, for the first time, we demonstrated that zinc oxide nanoparticles (ZnO NPs) were able to target multiple cell types of cancer, including cancer cells, cancer stem cells (CSCs), and macrophages, and simultaneously perform several key functions, including inhibition of cancer proliferation, sensitization of drug-resistant cancer, prevention of cancer recurrence and metastasis, and resuscitation of cancer immunosurveillance. As a nanocarrier, the chemotherapy drug, doxorubicin (Dox), could be loaded to ZnO NPs and the Dox-loaded ZnO NPs (ZnO/Dox) possessed excellent physicochemical and pH-responsive drug release properties. ZnO/Dox could be effectively internalized by both drug-sensitive and multidrug resistant (MDR) cancer cells and penetrate more efficiently through three-dimensional (3D) cancer cell spheroids compared with free Dox. As a cytotoxic agent, ZnO NPs were more efficient to kill MDR cancer cells. Interestingly, neither ZnO nor Dox showed high cytotoxicity in the 3D cancer cell spheroids, whereas ZnO/Dox showed remarkable synergistic anticancer effects. More importantly, we demonstrated that ZnO NPs could effectively downregulate CD44, a key CSC surface marker, and decrease the stemness of CSCs, leading to the sensitization of the Dox treatment, inhibition of the cancer cell adhesion and migration, and prevention of the tumor (3D cancer cell spheroid) formation. As an immunomodulator, ZnO NPs could protect macrophages from the Dox-induced toxicity and boost the Dox-induced macrophage polarization toward an M1-like phenotype. The macrophage-conditioned medium could promote the cancer cell apoptosis in both cancer cell monolayers and 3D spheroids. The findings in this study indicated that ZnO NPs were a multifunctional and multitarget nanocarrier and nanomedicine that would have more profound effects on cancer treatment.
由于癌症的复杂性，一种理想的抗癌策略更好地针对癌细胞和肿瘤微环境。在这项研究中，我们首次证明氧化锌纳米粒子（ZnO NPs）能够靶向多种癌细胞类型，包括癌细胞、癌症干细胞（CSCs）和巨噬细胞，并同时发挥多种关键功能，包括抑制癌细胞增殖、增敏耐药癌细胞、预防癌症复发和转移，以及恢复癌症免疫监视。作为一种纳米载体，化疗药物阿霉素（Dox）可以负载到 ZnO NPs 上，负载 Dox 的 ZnO NPs（ZnO/Dox）具有优异的物理化学性质和 pH 响应性药物释放特性。ZnO/Dox 可以被敏感和多药耐药（MDR）癌细胞有效内化，并比游离 Dox 更有效地穿透三维（3D）癌细胞球体。作为细胞毒性剂，ZnO NPs 对 MDR 癌细胞更有效。有趣的是，无论是 ZnO 还是 Dox 在 3D 癌细胞球体中都没有表现出高细胞毒性，而 ZnO/Dox 则表现出显著的协同抗癌作用。更重要的是，我们证明 ZnO NPs 可以有效地下调 CD44，一种关键的 CSC 表面标志物，并降低 CSCs 的干性，从而使 Dox 治疗更加敏感，抑制癌细胞黏附和迁移，并防止肿瘤（3D 癌细胞球体）形成。作为一种免疫调节剂，ZnO NPs 可以保护巨噬细胞免受 Dox 诱导的毒性，并促进 Dox 诱导的巨噬细胞向 M1 样表型极化。巨噬细胞条件培养基可以促进癌细胞在单层癌细胞和 3D 球体中的凋亡。本研究的结果表明，ZnO NPs 是一种多功能、多靶点的纳米载体和纳米药物，对癌症治疗将有更深远的影响。
