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, Universities of Shandong, Yantai University, Yantai, PR China.
Department of Radiotherapy, Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, PR China.
Drug Deliv. 2019 Dec;26(1):1265-1279. doi: 10.1080/10717544.2019.1693707.
In this study, the novel carrier materials were screened to structure targeting nano-micelles (named 'nano-dandelion') for synchronous delivery of curcumin (Cur) and baicalin (Bai), which could effectively overcome the tumor resistance. Mannose (Man) was found to bind better to CD206 receptors on the surface of tumor-associated macrophages (TAMs), thereby increasing the number of nano-dandelion engulfed by TAMs. Furthermore, oligomeric hyaluronic acid (oHA) was able to target CD44 receptors, resulting in recruitment of a higher number of nano-dandelion to locate and engulf tumor cells. The disulfide bond (S-S) in 3,3'-dithiodipropionic acid (DA) could be broken by the high concentration of glutathione (GSH) in the tumor microenvironment (TME). Based on this, we selected DA to connect hydrophobic fragments (quercetin, Que) and oHA. A reduction-sensitive amphiphilic carrier material, quercetin-dithiodipropionic acid-oligomeric hyaluronic acid-mannose-ferulic acid (Que-S-S-oHA-Man-FA; QHMF) was fabricated and synthesized by H NMR. Next, QHMF self-assembled into nano-dandelion, i.e. encapsulated Cur and Bai in water. Critical experimental conditions in the preparation process of nano-dandelion that could affect its final properties were explored. Nano-dandelion with a small particle size (121.0 ± 15 nm) and good normal distribution (PI = 0.129) could easily enter tumor tissue through vascular barrier. In addition, nano-dandelion with a suitable surface potential (-20.33 ± 4.02 mV) could remain stable for a long duration. Furthermore, good cellular penetration and tumor cytotoxicity of nano-dandelion were demonstrated through cellular studies. Finally, effective antitumor activity and reduced side effects were confirmed through antitumor experiments in A549 tumor-bearing nude mice.
在这项研究中，筛选了新型载体材料来构建靶向纳米胶束（命名为“纳米蒲公英”），用于同时递送姜黄素（Cur）和黄芩苷（Bai），可有效克服肿瘤耐药性。甘露糖（Man）被发现与肿瘤相关巨噬细胞（TAMs）表面的 CD206 受体结合更好，从而增加了 TAMs 吞噬纳米蒲公英的数量。此外，寡聚透明质酸（oHA）能够靶向 CD44 受体，导致更多的纳米蒲公英募集到肿瘤细胞定位和吞噬。3,3'-二硫代二丙酸（DA）中的二硫键（S-S）可被肿瘤微环境（TME）中高浓度的谷胱甘肽（GSH）打破。基于此，我们选择 DA 连接疏水性片段（槲皮素，Que）和 oHA。通过 1H NMR 合成了还原敏感的两亲性载体材料，即槲皮素-二硫代二丙酸-寡聚透明质酸-甘露糖-阿魏酸（Que-S-S-oHA-Man-FA；QHMF）。接下来，QHMF 自组装成纳米蒲公英，即将姜黄素和黄芩苷包封在水中。探索了制备纳米蒲公英的关键实验条件，这些条件会影响其最终性能。粒径较小（121.0 ± 15 nm）且分布良好（PI = 0.129）的纳米蒲公英很容易通过血管屏障进入肿瘤组织。此外，具有合适表面电位（-20.33 ± 4.02 mV）的纳米蒲公英能够长时间保持稳定。进一步通过细胞研究证明了纳米蒲公英具有良好的细胞穿透性和肿瘤细胞毒性。最后，通过 A549 荷瘤裸鼠的抗肿瘤实验证实了纳米蒲公英具有有效的抗肿瘤活性和降低的副作用。
