Department of Interventional and Vascular Surgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China; Center for Clinical and Translational Medicine, Shanghai University of Medicine & Health Sciences, Shanghai 201318, China; State Key Laboratory for Modification of Chemical Fibers and Polymer Materials, College of Materials Science and Engineering, Donghua University, Shanghai 201620, China.
State Key Laboratory for Modification of Chemical Fibers and Polymer Materials, College of Materials Science and Engineering, Donghua University, Shanghai 201620, China.
J Colloid Interface Sci. 2024 Aug 15;668:88-97. doi: 10.1016/j.jcis.2024.04.125. Epub 2024 Apr 18.
Nanotheranostic platforms, which can respond to tumor microenvironments (TME, such as low pH and hypoxia), are immensely appealing for photodynamic therapy (PDT). However, hypoxia in solid tumors harms the treatment outcome of PDT which depends on oxygen molecules to generate cytotoxic singlet oxygen (O). Herein, we report the design of TME-responsive smart nanotheranostic platform (DOX/ZnO@Zr-Ce6/Pt/PEG) which can generate endogenously hydrogen peroxide (HO) and oxygen (O) to alleviate hypoxia for improving photodynamic-chemo combination therapy of tumors. DOX/ZnO@Zr-Ce6/Pt/PEG nanocomposite was prepared by the synthesis of ZnO nanoparticles, in-situ assembly of Zr-Ce6 as typical metal-organic framework (MOF) on ZnO surface, in-situ reduction of Pt nanozymes, amphiphilic lipids surface coating and then doxorubicin (DOX) loading. DOX/ZnO@Zr-Ce6/Pt/PEG nanocomposite exhibits average sizes of ∼78 nm and possesses a good loading capacity (48.8 %) for DOX. When DOX/ZnO@Zr-Ce6/Pt/PEG dispersions are intratumorally injected into mice, the weak acidic TEM induces the decomposition of ZnO core to generate endogenously HO, then Pt nanozymes catalyze HO to produce O for alleviating tumor hypoxia. Upon laser (630 nm) irradiation, the Zr-Ce6 component in DOX/ZnO@Zr-Ce6/Pt/PEG can produce cytotoxic O, and O generation rate can be enhanced by 2.94 times due to the cascaded generation of endogenous HO/O. Furthermore, the generated O can suppress the expression of hypoxia-inducible factor α, and further enable tumor cells to become more sensitive to chemotherapy, thereby leading to an increased effectiveness of chemotherapy treatment. The photodynamic-chemo combination therapy from DOX/ZnO@Zr-Ce6/Pt/PEG nanoplatform exhibits remarkable tumor growth inhibition compared to chemotherapy or PDT. Thus, the present study is a good demonstration of a TME-responsive nanoplatform in a multimodal approach for cancer therapy.
肿瘤微环境（TME，如低 pH 值和缺氧）响应的纳米诊疗平台对于光动力疗法（PDT）极具吸引力。然而，实体瘤中的缺氧会损害 PDT 的治疗效果，因为 PDT 需要氧分子来产生细胞毒性单线态氧（O）。在此，我们报告了一种 TME 响应的智能纳米诊疗平台（DOX/ZnO@Zr-Ce6/Pt/PEG）的设计，该平台可以产生内源性过氧化氢（HO）和氧气（O）来缓解缺氧，从而提高肿瘤的光动力-化疗联合治疗效果。DOX/ZnO@Zr-Ce6/Pt/PEG 纳米复合材料是通过合成 ZnO 纳米粒子、Zr-Ce6 原位组装成典型的金属-有机骨架（MOF）在 ZnO 表面、Pt 纳米酶原位还原、两亲性脂质表面包覆以及随后负载阿霉素（DOX）来制备的。DOX/ZnO@Zr-Ce6/Pt/PEG 纳米复合材料的平均粒径约为 78nm，具有良好的 DOX 负载能力（48.8%）。当 DOX/ZnO@Zr-Ce6/Pt/PEG 分散体被注入小鼠肿瘤内时，弱酸性 TEM 诱导 ZnO 核分解产生内源性 HO，然后 Pt 纳米酶将 HO 催化产生 O 来缓解肿瘤缺氧。在激光（630nm）照射下，DOX/ZnO@Zr-Ce6/Pt/PEG 中的 Zr-Ce6 组分可以产生细胞毒性 O，并且由于内源性 HO/O 的级联产生，O 的产生速率可以提高 2.94 倍。此外，产生的 O 可以抑制缺氧诱导因子 α 的表达，从而使肿瘤细胞对化疗更敏感，从而提高化疗治疗的效果。与化疗或 PDT 相比，DOX/ZnO@Zr-Ce6/Pt/PEG 纳米平台的光动力-化疗联合治疗表现出显著的肿瘤生长抑制作用。因此，本研究很好地展示了 TME 响应的纳米平台在癌症治疗中的多模态方法。
