Mitochondrial targeting nanodrugs self-assembled from 9-O-octadecyl substituted berberine derivative for cancer treatment by inducing mitochondrial apoptosis pathways
Mitochondrial targeting nanodrugs self-assembled from 9-O-octadecyl substituted berberine derivative for cancer treatment by inducing mitochondrial apoptosis pathways
复制标题
由 9-O-十八烷基取代小檗碱衍生物自组装的线粒体靶向纳米药物通过诱导线粒体凋亡途径治疗癌症
DOI：
10.1016/j.jconrel.2018.11.014
复制
发表时间：
2019-01-28
影响因子：
10.8
通讯作者：
Hu, Haiyan
中科院分区：
文献类型：
--
作者：
Song, Jia;Lin, Chuchu;Hu, Haiyan
线粒体是理想的抗肿瘤靶点，因为线粒体在细胞凋亡和肿瘤抗凋亡中起着中枢调节作用。线粒体靶向给药存在一些挑战，包括复杂的多步制剂、低载药量和载体的全身毒性。为了解决这些问题，我们首先利用简单的纳米沉淀法，从9-O-十八烷基取代的黄连素衍生物(BD)中构建了线粒体靶向纳米颗粒。用DSPE-PEG2000(二硬脂酰磷脂酰乙醇胺-甲氧基聚乙二醇2000)对BD基纳米粒进行改性以提高稳定性。带负电荷的透明质酸(HA)被进一步包覆，以掩盖正电荷，实现肿瘤靶向。制备了表面电荷为-25.8 mV、载药量为70%的聚乙二醇二元改性BD-NDS(HA/PEG/BD-NDS)。透明质酸酶(Haase)在肿瘤组织中降解透明质酸，使带正电荷的聚乙二醇缩丁二醛(PEGBDNDS)暴露于细胞内，有利于细胞摄取，进而促进溶酶体逃逸和线粒体靶向。通过线粒体膜电位的降低、细胞色素C的释放、caspase 9/3活性的升高、促凋亡基因Bax的激活、抗细胞凋亡基因Bcl2的表达以及ROS水平的上调来诱导细胞凋亡。在A549移植瘤模型中，HA/PEG/BD NDS具有明显的肿瘤细胞线粒体靶向性和显著的抗肿瘤作用。总体而言，与传统的纳米粒子相比，线粒体靶向HA/PEG/BD NDS为肿瘤治疗提供了一种新的策略，具有更高的载药量、相对简单的制备工艺和较低的载体毒性。
Mitochondria are ideal anti-tumor target due to mitochondria's central regulation role in cell apoptosis and tumor resistance to apoptosis. There are several challenges for mitochondrial targeting drug delivery, including complex multistep preparations, low drug-loading and systemic toxicity from the carriers. To address these issues, we firstly constructed mitochondria-targeting nanodrugs self-assembled from 9-O-octadecyl substituted berberine derivative (BD) using simple nano-precipitation approach. BD-based nanodrugs were modified by DSPE-PEG2000 (distearylphosphatidylethanolamine- methoxypolyethylene glycol 2000) to increase stability. Negatively charged hyaluronic acid (HA) was further coated to conceal positive charges and achieve tumor targeting. PEG and HA dually modified BD NDs (HA/PEG/BD NDs) were prepared with surface charge of -25.8 mV and high drug loading > 70%. The degradation of HA by hyaluronidase (HAase) at tumor tissue allowed the exposure of the positively charged PEG/BD NDs to the cells, which is beneficial for cell uptake and further lysosome escape and mitochondrial targeting. Then, HA/PEG/BD NDs were investigated to induce apoptosis through dissipating mitochondria membrane potential, releasing cytochrome C, increasing the activities of caspase 9/3, activating the pro-apoptotic Bax, suppressing the anti-apoptotic Bcl-2 and upregulating ROS levels. In the A549 xenografted tumor model, HA/PEG/BD NDs exhibited obvious tumor cell mitochondrial targeting and significant anti-tumor efficacy. Overall, comparing to conventional nanoparticles, mitochondrial targeting HA/PEG/BD NDs provide a new strategy for cancer treatment with enhanced drug-loading, relatively simplified preparation processes and reduced carrier toxicities.