A two-step precise targeting nanoplatform for tumor therapy via the alkyl radicals activated by the microenvironment of organelles.
【作者】Wang, Lei; Niu, Xiuxiu; Song, Qingling; Jia, Jiajia; Hao, Yongwei ; Zheng, Cuixia; Ding, Kaili ; Xiao, Huifang ;Liu, Xinxin ; Zhang, Zhenzhong ; Zhang, Yun
【作者单位】 School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou 450001, PR China【期刊名】JOURNAL OF CONTROLLED RELEASE
【影响因子】2018年：7.901
【年，卷(期)：页码】2020, 318: 197-209
【关键词】Mitochondrial temperature; Alkyl radicals; Two-step targeting; pH-sensitive
【摘要】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 conditionfor tumortherapy. Based on this, we constructed a two-stepprecise 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,andthecore-shell AIPH/MSN-TPP@Lipo/DTX-FA nanoparticles were constructedby self-assembly during thehydration 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. Afterthat,AIPHwas delivered to mitochondriabyAIPH/MSN-TPP, and the alkyl radicals produced by AIPH under the high temperature environment can cause oxidativedamagetomitochondria.Notonly that,theDTXcould 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 tumortherapy.
【全文链接】https://doi.org/10.1016/j.jconrel.2019.10.017
