A Two-Step Precise Targeting Nanoplatform for Tumor Therapy via the Alkyl Radicals Activated by the Microenvironment of Organelles.
A Two-Step Precise Targeting Nanoplatform for Tumor Therapy via the Alkyl Radicals Activated by the Microenvironment of Organelles.
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DOI：
10.1016/j.jconrel.2019.10.017
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发表时间：
2020-02
期刊：
影响因子：
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通讯作者：
Lei Wang;Xiuxiu Niu;Qingling Song;Jiajia Jia;Yongwei Hao;Cuixia Zheng;Kaili Ding;H. Xiao
中科院分区：
文献类型：
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作者：
Lei Wang;Xiuxiu Niu;Qingling Song;Jiajia Jia;Yongwei Hao;Cuixia Zheng;Kaili Ding;H. Xiao
随着对细胞器研究的深入，细胞器自身所具有的微环境特性，如溶酶体的酸性环境和线粒体的高温环境，可以作为肿瘤治疗的天然而有力的条件。在此基础上，我们构建了一个两步精确靶向的纳米平台，可以实现药物的释放和药物的作用分别由溶酶体（内体）和线粒体的微环境触发。开始，用三苯基磷（TPP）修饰介孔二氧化硅纳米粒子（MSNs），并负载2，2 ′-偶氮二[2-（2-咪唑啉-2-基）丙烷]二盐酸盐（AIPH）。采用薄膜分散法制备叶酸靶向多西他赛pH敏感脂质体（Lipo/DTX-FA），并在脂质体水化过程中自组装成核壳结构的AIPH/MSN-TPP@Lipo/DTX-FA纳米粒。当这种纳米平台通过FA受体介导的内吞作用进入肿瘤细胞时，pH敏感性脂质体在溶酶体中不稳定，导致DTX和AIPH/MSN-TPP纳米颗粒的释放。之后，AIPH/MSN-TPP将AIPH递送到线粒体，并且AIPH在高温环境下产生的烷基自由基可对线粒体造成氧化损伤。结果表明，DTX可通过下调抗凋亡Bcl-2蛋白的表达，增强AIPH的抗肿瘤作用。体内外实验结果表明，该系统能够利用细胞器自身的微环境诱导细胞凋亡，为肿瘤治疗提供了新的途径。
With the in-depth research of organelles, the microenvironment characteristics of their own, such as the acid environment of lysosomes and the high temperature environment of mitochondria, could be used as a natural and powerful condition for tumor therapy. Based on this, we constructed a two-step precise targeting nanoplatform which can realize the drug release and drug action triggered by the microenvironment of lysosomes (endosomes) and mitochondria, respectively. To begin with, the mesoporous silica nanoparticles (MSNs) were modified with triphenylphosphonium (TPP) and loaded with 2,2′-azobis[2-(2-imidazolin-2-yl) propane] dihydrochloride (AIPH). Then, folic acid (FA) targeted pH-sensitive liposomes containing docetaxel (Lipo/DTX-FA) were prepared by thin-film dispersion method, and the core-shell AIPH/MSN-TPP@Lipo/DTX-FA nanoparticles were constructed by self-assembly during the hydration of the liposomes. When this nanoplatform entered into the tumor cells through FA receptor-mediated endocytosis, the pH-sensitive liposomes were destabilized in the lysosomes, resulting in the release of DTX and AIPH/MSN-TPP nanoparticles. After that, AIPH was delivered to mitochondria by AIPH/MSN-TPP, and the alkyl radicals produced by AIPH under the high temperature environment can cause oxidative damage to mitochondria. Not only that, the DTX could enhance the anti-tumor effect of AIPH by downregulating the expression of anti-apoptotic Bcl-2 protein. The in vitro and in vivo results demonstrate that this delivery system could induce apoptosis based on organelles’ s own microenvironment, which provides a new approach for tumor therapy.