In this work, we developed a novel technique to prepare pH-responsive charge reversal nanospheres based on softwood kraft lignin (SKL) through two steps modification and high efficient self-assembly. SKL was first grafted with imidazole groups by Mannich reaction and further fabricated into acetylated histidine-modified lignin (AceSKL-HIS) via acetylation reaction. Ace-SKL-HIS nanospheres (Ace-SKL-HIS NPs) were prepared by fast vacuum evaporation method, their effective diameters (ED) were around 100 nm, exhibited low Polydispersity Index(PDI, < 0.2) and good shape. Ace-SKL-HIS NPs demostrated excellent pH response performance with charge reversal under acidic environment. Then, curcumin was applied as a model drug to prepare drug-loaded nanospheres (Ace-SKL-HIS@CUR). The drug loading degree (DL%) and encapsulation efficiency (EE%) were 22.34 % and 70.76 %, respectively. The in vitro release behavior of curcumin exhibited excellent pH dependent release property, 76.82 % release at pH 5.7 while only 12.92 % at pH 7.4 in 120 h. Furthermore, in vitro cytotoxicity studies showed that Ace-SKL-HIS@CUR had potent anti-tumor effect, with IC50 of 28.16 mu g/mL. This study constructed a promising nanocarrier platform for cancer drug delivery, which paved a new way to the high valueadded application of lignin.

生物基来源的聚合物具有生物相容性高、无毒易降解等优势,近些年来作为药物载体在生物医药领域受到了广泛的关注.人体内的生理环境存在pH差异,利用pH作为刺激响应的信号,可以赋予聚合物纳米载药系统理想的靶向释药性能.本综述着眼于pH敏感性的生物基聚合物纳米粒子,揭示了纳米载药粒子中化学键断裂与质子化作用两种pH响应的控释机制,并针对两者的控释特点进行了分析总结.在此基础上,介绍了几种生物基药物载体的pH控释研究及其在生物医药领域的应用进展,并提出了目前利用各种生物基材料作为药物载体存在的问题.最后,针对目前存在的载药量低、敏感性不强等问题,提出了可采用多种方式联合载药、多重刺激响应结合等方式进行深入研究的展望.

In this study, we establish a novel highly efficient preparation process to prepare homogeneous and size controllable pH-responsive lignin nanosphere (LN). Orthogonal experiments have been performed to investigate the effects of the factors (bath temperature, lignin concentration, starting volume, cooling temperature) on the effective diameters (ED) and polydispersity index (PDI) of LN. The fast vacuum evaporation process could also encapsulate drugs in the one-pot process, with the solvent acetone recycled simultaneously. The drug release based on pH-responsive have been investigated. As a result, homogenous LN with targeted size (within 100 similar to 400 nm) had been obtained under the preparation conditions suggested by the established Models. The matrix entrapment efficiency of LN was 47 %. The lignin encapsulating Ibuprofen nanospheres showed excellent pH responsive release. It had just 18 % released at pH 1.2, while over 90 % at pH7.5 for 2-6 h. This study introduced a highly efficient way to prepare lignin nanospheres and a new strategy to prepare pH-responsive drugs.