原文献：pH-Responsive Dual Drug-Loaded Nanocarriers Based on Poly (2-Ethyl-2-Oxazoline) Modified Black Phosphorus Nanosheets for Cancer Chemo/Photothermal Therapy

文献链接：https://xueshu.baidu.com/usercenter/paper/show?paperid=5f3f28ee8a8e7f788a2f2158047217f5&site=xueshu_se&hitarticle=1

作者：Nansha Gao, Chenyang Xing, Haifei Wang, Liwen Feng, Xiaowei Zeng, Lin Mei and

Zhengchun Peng

原文摘要：Synergistic cancer therapy, such as those combining chemotherapeutic and photothermal methods, has stronger treatment effect than that of individual ones.However, it is challenging to efficiently deliver nanocarriers into tumor cells to elevate intracellular drug concentration. Herein, we developed an effective pH-responsive and dual drug co-delivery platform for combined chemo/photothermal therapy. An anticancer drug doxorubicin (DOX) was first loaded onto the surface of black phosphorus (BP). With poly(2-ethyl-2-oxazoline) (PEOz) ligand conjugated onto the polydopamine (PDA) coated BP nanosheets, targeted long circulation and cellular uptake in vivo was significantly improved. With another anticancer drug bortezomib (BTZ) loaded onto the surface of the nanocapsule, the platform can co-deliver two different drugs. The surface charge of the nanocapsule was reversed from negative to positive at the tumor extracellular pH (∼6.8), ionizing the tertiary amide groups along the PEOz chain, thus facilitating the cell internalization of the nanocarrier. The cytotoxicity therapeutic effect of this nanoplatform was further augmented under near-infrared laser irradiation. As such, our DOX-loaded BP@PDA-PEOz-BTZ platform is very promising to synergistic cancer therapy.

ph响应和双化合物共传递平台，将纳米载体导入tumor细胞以提高细胞内化合物浓度，用于联合应用。阿霉素（DOX）首先被装载到黑磷（BP）的表面。将聚（2-乙基-2-恶唑啉）（PEOz）配体偶联到聚多巴胺（PDA）涂层的BP纳米片上，体内靶向长循环和细胞摄取改善。在tumor胞外pH（∼6.8）处，纳米胶囊的表面电荷从负转为正，电离沿PEOz链的叔酰胺基团，从而促进纳米载体的细胞内化。制备过程如下：

图：阿霉素

BP NSs的制备

将相应的BP样品在液体中剥离，制备黑磷NSs。将BP分散在1-甲基-2-吡咯烷酮（NMP）中，通过氩气起泡，通过消除剥离过程中的溶解氧分子来减少氧化。然后将混合物在冰水浴中超声,离心,去除未剥离的大块BP，并仔细收集含有BP NSs的上清液以供进一步使用。

DOX加载到BP NS表面

将阿霉素与BPNSs溶液水中混合，用氢氧化钠调整溶液pH。在黑暗中剧烈搅拌过夜后，通过离心收集获得的装载dox的BP（BP-DOX）NSs，并用水洗涤。

BP NS表面的PDA涂层

BP-DOX NSs分散在HyPure分子生物学级水中然后加入氢氧化钠调节pH加入多巴胺盐酸盐，室温黑暗搅拌。最后离心收集BP-DOX@PDA颗粒，用去离子水洗涤。

H2N-PEOz或H2N-PEG在BP-DOX@PDA表面上的结合

pda包覆的NSs首先在HyPure分子生物学级水中重悬，用适当数量的氢氧化钠调整pH。在BP@PDA悬浮液中加入h2NPEOz后，在室温黑暗中剧烈搅拌。然后将h2n-PEOz修饰的NPs（BP-DOX@PDA-PEOz离心纯化，用去离子水洗涤。

BTZ加载到pda涂层的NPs上

将BP-DOX@PDA-PEOz NPs悬浮在去离子水中，用氢氧化钠调节pH,BTZ粉末分散在的DMSO中。在搅拌条件下，然后将后一种溶液滴加到前一种溶液中。然后，将混合物搅拌过夜，并按照上述相同的方法离心。在冻干后，该产品被称为BP-DOX@PDA-PEOz-BTZ。

图：BP-DOX@PDA-PEOz-BTZ的制备过程

结论：NH2-PEOz的末端胺基通过简单的Michalel加成反应与被PDA包裹的NSs结合。PEOz作为一种长链分子，PEOz作为PEG的替代品被引入该体系，以维持长期循环，减弱ABC现象，并允许ph反应性化合物的释放。装载dox的BP@PDA-PEOz-BTZ可通过延长体内循环、提高细胞摄取效率、pH反应性和双重载化合物能力，经过PDA和PEOz涂层后，NS表面变得粗糙，并略有增厚。