Hosseinifar Nastaran, Goodarzi Navid, Sharif Amir Abdolah Mehrdad, Amini Mohsen, Esfandyari-Manesh Mehdi, Dinarvand Rassoul
Department of Applied Chemistry, Faculty of Chemistry, Islamic Azad University Tehran-North Branch, Iran.
Nanotechnology Research Centre, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.
Drug Res (Stuttg). 2020 Feb;70(2-03):71-79. doi: 10.1055/a-1016-6889. Epub 2020 Jan 27.
Mitochondria have been recognized as important targets in cancer therapy due to their role in the respiratory process of cells. One approach employed for mitochondrion targeting is conjugation of a delocalized cation such as triphenylphosphonium (TPP), with antineoplastic agents, for instance paclitaxel (PTX). In cell cytoplasm, TPP-PTX can come close to mitochondria due to its high positive charge, which has a strong tendency toward the enhanced negative charge of mitochondria. The esteric bond of TPP-PTX can break down in the acidic environment of tumor cells and release the PTX, which can act directly on mitochondria to kill tumor cells. TPP-PTX was synthesized in three steps: Succinic anhydride (SUC) reacted with PTX to achieve succinyl paclitaxel (SUC-PTX), which has an acid-labile esteric bond. Then 2-triphenylphosphonium ethylammonium (ATPP) was prepared by attaching 2-bromoethylammunium bromide to TPP. Finally, a TPP-PTX prodrug was synthesized by attaching these materials. The products of all steps were characterized by thin-layer chromatography (TLC), infrared spectroscopy (IR), and nuclear magnetic resonance (H NMR, C NMR). The purity of the products was determined by HPLC methods. TPP-PTX, as a prodrug, was loaded in to human serum albumin (HSA) nanoparticles by a method inspired by nab-technology with 130-160 nm particle size distribution, PdI=0.166 and Zeta potential -12.6 mV.
由于线粒体在细胞呼吸过程中的作用，其已被公认为癌症治疗中的重要靶点。一种用于线粒体靶向的方法是将诸如三苯基膦（TPP）之类的离域阳离子与抗肿瘤药物（例如紫杉醇（PTX））缀合。在细胞质中，TPP-PTX因其高正电荷而可接近线粒体，该正电荷对线粒体增强的负电荷具有很强的趋向性。TPP-PTX的酯键可在肿瘤细胞的酸性环境中分解并释放PTX，PTX可直接作用于线粒体以杀死肿瘤细胞。TPP-PTX通过三步合成：琥珀酸酐（SUC）与PTX反应得到具有酸不稳定酯键的琥珀酰紫杉醇（SUC-PTX）。然后通过将2-溴乙铵溴化物连接到TPP上制备2-三苯基膦乙铵（ATPP）。最后，通过连接这些物质合成TPP-PTX前药。所有步骤的产物通过薄层色谱（TLC）、红外光谱（IR）和核磁共振（H NMR、C NMR）进行表征。产物的纯度通过HPLC方法测定。TPP-PTX作为前药，通过受纳米白蛋白紫杉醇（nab）技术启发的方法负载到人血清白蛋白（HSA）纳米颗粒中，粒径分布为130 - 160nm，多分散指数（PdI）=0.166，zeta电位为-12.6mV。
