Overcoming chemotherapy resistance using pH-sensitive hollow MnO(2) nanoshells that target the hypoxic tumor microenvironment of metastasized oral squamous cell carcinoma.
Overcoming chemotherapy resistance using pH-sensitive hollow MnO(2) nanoshells that target the hypoxic tumor microenvironment of metastasized oral squamous cell carcinoma.
复制标题
DOI：
10.1186/s12951-021-00901-9
复制
发表时间：
2021-05-26
影响因子：
10.2
通讯作者：
Zhong LP
中科院分区：
文献类型：
--
作者：
Zhou ZH;Liang SY;Zhao TC;Chen XZ;Cao XK;Qi M;Huang YY;Ju WT;Yang M;Zhu DW;Pang YC;Zhong LP
针对酸性肿瘤微环境(TME)的智能纳米药物输送系统可以提供药物的受控释放，并调节缺氧的TME以加强癌症治疗。以前报道的大多数MnO2纳米结构是纳米颗粒、纳米片状颗粒或与其他类型的纳米颗粒结合的纳米复合材料，这可能不能提供最有效的药物加载或治疗有效载荷释放的方法。以前的研究已经设计了MnO2纳米壳，实现了对局部晚期癌症的肿瘤特异性和增强型联合治疗。然而，二氧化锰纳米壳对转移性癌症的治疗效果仍不确定。本研究基于中空介孔MnO2(H-MnO2)纳米壳负载化疗药物多西紫杉醇和顺铂(TP)形成H-MnO2-PEG/TP纳米壳，用于缓解肿瘤缺氧、抑制血管生成、触发Mn2+的溶解，并协同一流抗癌化疗的疗效。得到的H-MnO_2-聚乙二醇/TP纳米壳在酸性的TME中分解，释放负载的药物(TP)，同时通过诱导内源性肿瘤过氧化氢(H_2O_2)分解来减弱肿瘤缺氧和缺氧诱导因子-1α(H IF-1α)的表达。体外实验表明，与对照组相比，H-MnO2-聚乙二醇组CAL27和SCC7细胞的增殖、克隆形成和迁移能力明显降低，细胞凋亡率增加，低氧诱导因子-1α(HIF-1α)表达下调。体内实验表明，H-MnO2-PEG/TP组小鼠肿瘤与正常器官的摄取率(T/N比)明显高于单纯TP组(不含纳米颗粒)，肿瘤生长部分延迟。H-MnO2-PEG/TP治疗组HE染色显示大部分肿瘤细胞损伤严重，TUNEL法检测显示细胞凋亡上调。肾、肝切片HE染色未见明显纤维化、坏死或肥大，生物安全性良好。荧光染色显示HIF-1α表达降低，提示肿瘤中MnO2的积聚导致了H_2O_2分解为O_2，从而缓解了肿瘤的缺氧。综上所述，TP联合化疗在体内、外协同治疗效果显著，同时引发了一系列抗血管生成和氧化抗肿瘤反应。网上版载有补充材料，可在10.1186/s12951-021-00901-9查阅。
Smart nanoscale drug delivery systems that target acidic tumor microenvironments (TME) could offer controlled release of drugs and modulate the hypoxic TME to enhance cancer therapy. The majority of previously reported MnO2 nanostructures are nanoparticles, nanosheets, or nanocomposites incorporated with other types of nanoparticles, which may not offer the most effective method for drug loading or for the controlled release of therapeutic payloads. Previous studies have designed MnO2 nanoshells that achieve tumor-specific and enhanced combination therapy for localized advanced cancer. However, the therapeutic effect of MnO2 nanoshells on metastatic cancer is still uncertain. Here, intelligent “theranostic” platforms were synthesized based on hollow mesoporous MnO2 (H-MnO2) nanoshells that were loaded with chemotherapy agents docetaxel and cisplatin (TP) to form H-MnO2-PEG/TP nanoshells, which were designed to alleviate tumor hypoxia, attenuate angiogenesis, trigger the dissolution of Mn2+, and synergize the efficacy of first-class anticancer chemotherapy. The obtained H-MnO2-PEG/TP nanoshells decomposed in the acidic TME, releasing the loaded drugs (TP) and simultaneously attenuated tumor hypoxia and hypoxia-inducible factor-1α (HIF-1α) expression by inducing endogenous tumor hydrogen peroxide (H2O2) decomposition. In vitro experiments showed that compared with the control group, the proliferation, colony formation and migration ability of CAL27 and SCC7 cells were significantly reduced in H-MnO2-PEG/TP group, while cell apoptosis was enhanced, and the expression of hypoxia-inducible factor-1α(HIF-1α) was down-regulated. In vivo experiments showed that tumor to normal organ uptake ratio (T/N ratio) of mice in H-MnO2-PEG/TP group was significantly higher than that in TP group alone (without the nanoparticle), and tumor growth was partially delayed. In the H-MnO2-PEG/TP treatment group, HE staining showed that most of the tumor cells were severely damaged, and TUNEL assay showed cell apoptosis was up-regulated. He staining of renal and liver sections showed no obvious fibrosis, necrosis or hypertrophy, indicating good biosafety. Fluorescence staining showed that HIF-1α expression was decreased, suggesting that the accumulation of MnO2 in the tumor caused the decomposition of H2O2 into O2 and alleviated the hypoxia of the tumor. In conclusion, a remarkable in vivo and in vitro synergistic therapeutic effect is achieved through the combination of TP chemotherapy, which simultaneously triggered a series of antiangiogenic and oxidative antitumor reactions. The online version contains supplementary material available at 10.1186/s12951-021-00901-9.
登录
查看更多内容
影响因子：
15
作者：
Barandov A;Bartelle BB;Gonzalez BA;White WL;Lippard SJ;Jasanoff A
通讯作者：
Jasanoff A
叶酸共轭二氧化硅修饰的金纳米棒用于 X 射线/CT 成像引导的双模辐射和光热治疗
影响因子：
14
作者：
Huang, Peng;Bao, Le;Cui, Daxiang
通讯作者：
Cui, Daxiang
影响因子：
29.4
作者：
Chen, Qian;Feng, Liangzhu;Liu, Zhuang
通讯作者：
Liu, Zhuang
影响因子：
30.8
作者：
Bhandari, Vinayak;Hoey, Christianne;Bristow, Robert G.
通讯作者：
Bristow, Robert G.
影响因子：
37.3
作者：
Nomura T;Yamasaki M;Hirai K;Inoue T;Sato R;Matsuura K;Moriyama M;Sato F;Mimata H
通讯作者：
Mimata H