School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai 264005, PR China.
Medical Center, the Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, Shandong, 264000, PR China.
Carbohydr Polym. 2020 Apr 15;234:115930. doi: 10.1016/j.carbpol.2020.115930.
Mitochondrial targeting drug delivery systems have made unprecedented progress in tumor treatment. Nevertheless, the stability of systemic circulation and the effectiveness of tumor accumulation are the basis for achieving tumor subcellular targeting. This study aims to overcome the biological barrier while improving the mitochondria-targeted effect of nanoparticles based on natural polysaccharides. Novel polysaccharide-based nanoparticles, with tumor microenvironment-responsive charge-reversal and mitochondrial targeting abilities, were prepared in our study. Curcumin (Cur) was loaded into the core of a positively charged chitosan oligosaccharide (COS) derivative with mitochondrial targeting ability, and a negatively charged shell based on angelica sinensis polysaccharide (AS) derivative was wrapped in the surface of the core. At the same time, the pH-sensitive borate ester bond was formed between the shell and the core. In vitro experiments showed that mitochondrial-targeted core-shell nanoparticles achieved charge-reversal and release more Cur in the acidic tumor microenvironment. After entering into the tumor cells, the lysosomes escape was effectively realized, and more Cur was transmitted to the mitochondria. This process led to the enhancement of the cytotoxicity, the reduction of the mitochondrial membrane potential and the activation of the apoptotic pathway. The results of in vivo experiments showed that the core-shell nanoparticles efficiently delivered the drug to the tumor site and significantly prolonged the retention time of the drug in the tumor tissue. At the same time, it had excellent antitumor activity and in vivo safety for tumor-bearing nude mice.
线粒体靶向药物传递系统在肿瘤治疗方面取得了前所未有的进展。然而，系统循环的稳定性和肿瘤积累的有效性是实现肿瘤亚细胞靶向的基础。本研究旨在克服生物屏障，同时提高基于天然多糖的纳米粒子的线粒体靶向效应。我们研究了一种新型基于多糖的纳米粒子，具有肿瘤微环境响应的荷负电反转和线粒体靶向能力。姜黄素（Cur）被装载到具有线粒体靶向能力的壳聚糖寡糖（COS）衍生物的正电荷核心中，并在核心表面包裹基于当归多糖（AS）衍生物的负电荷壳。同时，壳和核之间形成 pH 敏感的硼酸酯键。体外实验表明，线粒体靶向的核壳纳米粒子在酸性肿瘤微环境中实现了荷负电反转，并释放出更多的 Cur。进入肿瘤细胞后，有效地实现了溶酶体逃逸，更多的 Cur 被传递到线粒体。这一过程增强了细胞毒性，降低了线粒体膜电位，并激活了凋亡途径。体内实验结果表明，核壳纳米粒子有效地将药物递送到肿瘤部位，并显著延长了药物在肿瘤组织中的滞留时间。同时，它对荷瘤裸鼠具有优异的抗肿瘤活性和体内安全性。
