Tumor Microenvironment-Responsive, Multistaged Liposome Induces Apoptosis and Ferroptosis by Amplifying Oxidative Stress for Enhanced Cancer Therapy.,ACS Applied Materials & Interfaces

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Tumor Microenvironment-Responsive, Multistaged Liposome Induces Apoptosis and Ferroptosis by Amplifying Oxidative Stress for Enhanced Cancer Therapy.
ACS Applied Materials & Interfaces ( IF 8.3 ) Pub Date : 2020-05-27 , DOI: 10.1021/acsami.0c03564
Longfa Kou ₁ , Rui Sun ₁ , Xinyu Jiang _{1,

2} , Xinlu Lin ₁ , Huirong Huang ₁ , Shihui Bao ₁ , Youting Zhang ₁ , Chao Li ₃ , Ruijie Chen ₁ , Qing Yao _{1,

2}

Affiliation

Tumor cells usually display metabolic, genetic, and microenvironment-related alterations, which are beneficial to tumor proliferation, tumor development, and resistance occurrence. Many transporters and enzymes, including ATB^0,+, xCT, and matrix metalloproteinases (MMPs), are involved in the altered cell metabolism and tumor microenvironment and often abnormally upregulated in malignant tumors. Meanwhile, these dysregulated transporters and enzymes provide targets not only for a pharmacological blockage to suppress tumor progress but also for tumor-specific delivery. Although transporters and MMPs have been widely reported for antitumor drug delivery, the feasibility of utilizing two strategies has never been elucidated yet. Herein, we developed an MMP2-activated and ATB^0,+-targeted liposome with doxorubicin and sorafenib (DS@MA-LS) loaded for optimal tumor drug delivery for cancer therapy. DS@MA-LS was designed to prolong blood circulation and deshield the PEG shell from MMP2 cleavage to expose lysine and target overexpressed ATB^0,+ for enhanced tumor distribution and cancer cellular uptake. Besides the anticancer effects of loaded drugs, the endocytosed liposomes could further increase ROS production and suppress the antioxidant system to amplify oxidative stress. As expected, DS@MA-LS displayed enhanced targeted drug delivery to tumor sites with the MMP2-controlled ligand exposure and ATB^0,+-mediated uptake. More importantly, DS@MA-LS successfully inhibited the tumor growth and cancer cell proliferation both in vitro and in vivo by enhancing apoptosis and ferroptosis, which thanks to the increased ROS generation and impaired GSH synthesis synergistically amplified oxidative stress. Our results suggested that the tumor microenvironment-responsive, multistaged nanoplatform, DS@MA-LS, has excellent potential for optimal drug delivery and enhanced cancer treatment.

中文翻译：

肿瘤微环境响应性多级脂质体通过放大氧化应激以增强癌症治疗来诱导细胞凋亡和肥大症。

肿瘤细胞通常表现出与代谢，遗传和微环境有关的改变，这有利于肿瘤增殖，肿瘤发展和耐药性的发生。许多转运蛋白和酶，包括ATB ^0，+，xCT和基质金属蛋白酶（MMP），都参与了细胞代谢和肿瘤微环境的改变，在恶性肿瘤中通常异常上调。同时，这些失调的转运蛋白和酶不仅为抑制肿瘤进展的药理学阻断提供了靶标，而且为肿瘤特异性的传递提供了靶标。尽管转运蛋白和MMP已被广泛报道用于抗肿瘤药物的输送，但尚未阐明利用两种策略的可行性。在这里，我们开发了M MP2激活和ATB ^0，+靶向性升IPO小号OME与d oxorubicin和小号orafenib加载最佳肿瘤药物递送用于癌症治疗（DS @ MA-LS）。DS @ MA-LS设计用于延长血液循环，并从MMP2裂解中解开PEG外壳，以暴露赖氨酸并靶向过表达的ATB 0+ ^，以增强肿瘤分布和癌细胞摄取。除了负载药物的抗癌作用外，内吞脂质体还可以进一步增加ROS的产生并抑制抗氧化系统以放大氧化应激。正如预期的那样，DS @ MA-LS通过MMP2控制的配体暴露和ATB ^0，+显示出增强的靶向药物递送至肿瘤部位的能力介导的摄取。更重要的是，DS @ MA-LS成功地抑制两个肿瘤生长和癌细胞增殖的体外和体内通过增强细胞凋亡和ferroptosis，这得益于增加ROS产生和受损的GSH合成协同放大氧化应激。我们的结果表明，肿瘤微环境响应性多阶段纳米平台DS @ MA-LS具有最佳的药物递送和增强的癌症治疗潜力。

更新日期：2020-05-27

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