文献：Metformin-hydrogel with glucose responsiveness for chronic inflammatory suppression

文献链接：https://xueshu.baidu.com/usercenter/paper/show?paperid=1g050rc0c42308g0u37k0jp0f3051728&site=xueshu_se

作者：Dandan Zheng, Wei Chen , Huitong Ruan, Zhengwei Cai, Xiuyuan Chen, Tongtong Chen ,

Yuhui Zhang, Wenguo Cui , Hao Chen , Hongxing Shen

相关产品：DSPE-PEG2000-PBA 磷脂-聚乙二醇2000-苯硼酸

原文摘要：Diabetes-induced chronic inflammation accelerates tissue degeneration and is difficult to cure due to the persistent pathological high-glucose microenvironment. Herein, a

glucose-responsive drug delivery system was constructed by conjugating phenylboronic acid on the surface of liposomes via membrane insertion and further crosslinked into a glucosamine-modified hydrogel composed of hyaluronic acid (HA)

andpoly(ethylene glycol) diacrylate (PEG) through borate linkages to deliver metformin, which could achieve the

anti-inflammation effect under high glucose condition (Met@HA-PEG).The release kinetics results revealed that Met@HA-PEG could adjust the amount of metformin by responding to the change of glucose concentrations. It is proved that Met@HA-PEG could protect mitochondria from ROS, thereby inhibiting the activation of the NLRP3 inflam matory pathway and finally increasing the synthesis of extracellular matrix (ECM) in the nucleus pulposus cells compared to the high glucose-treated group. In vivo experiments showed that Met@HA-PEG could effectively promote tissue regeneration in the diabetes-induced intervertebral disc degeneration model rats by inhibiting high glucose-induced chronic inflammation and stimulating ECM synthesis. Overall, a drug delivery system with glucose sensitivity was designed to achieve the spatiotemporal release of metformin, the long-term antiinflammation and promotion of ECM synthesis which ensures the smooth completion of tissue regeneration under diabetic conditions.

DSPE-PEG2000-PBA 是一种由二硬脂酰磷脂酰乙醇胺（DSPE）、聚乙二醇 2000（PEG2000）和苯硼酸（PBA）组成的化合物。DSPE 具有良好的生物相容性和疏水性，是构建脂质纳米颗粒和脂质体的常用材料。PEG2000 可以增加材料的水溶性、稳定性，并减少与生物体组织的非特异性相互作用。PBA 能够与一些生物分子如葡萄糖特异性结合，赋予材料靶向性。该产品作为靶向给药系统的组成部分，实现针对特定细胞或组织的化合物传递，也在生物传感器、生物成像和组织工程等领域有应用潜力。该文献将葡萄糖反应苯硼酸结合在脂质体表面，通过硼酸键交联到由透明质酸（HA）和聚（乙二醇）葡萄糖胺修饰的水凝胶中传递二甲双胍（Met@HA-PEG）。过程如下：

图：Met@HA-PEG的建设

PBA-脂质体的合成

制备空白或二甲双胍装载pba表面修饰脂质体并进行表征。简单地说，将磷脂酰胆碱、胆固醇和DSPE-PEG-PBA溶解在氯仿中，蒸发形成脂质膜。然后用含或不含二甲双胍的PBS水合薄膜，然后超声检查，然后通过滤。最后，将获得的脂质体加入超滤管（微孔）中，离心，以去除游离的二甲双胍。收集浓缩的脂质体用于后续实验。

NH2-葡萄糖修饰HA甲基丙烯酸酯（NH2-Gluc HAMA）的合成

将HA加入去离子水中，通过机械搅拌溶解。将溶液冷却后，将MA溶液与HA溶液混合。然后，将氢氧化钠溶液滴加入反应体系，在冰浴下继续反应。最后，透析溶液，冻干获得纯HAMA。然后，通过DMTMM偶联反应制备NH2-gluc HAMA。将HAMA溶解于 2-（N-吗啉）乙磺酸（MES）缓冲液中。将nh2-葡萄糖和DMTMM分别溶于DMSO和去离子化水中，在搅拌下同时滴加入上述溶液中。该混合物在室温下反应过夜。然后将产品溶液转移到透析袋中，用氯化钠溶液透析，然后用去离子水透析。最后，将溶液冻干得到NH2-gluc HAMA。

HA-PEG水凝胶和Met@HA-PEG水凝胶的制备

采用NH2-Gluc HAMA和4臂PEGDA制备HA-PEG水凝胶。简单地说，将一定量的NH2-Gluc HAMA和4-臂PEGDA溶解在PBS中。然后加入过硫酸铵和TEMED使溶液剧烈涡旋。最后，将溶液注入或保存在氮气下进行凝胶化。将MET@脂质液加入到 HA-PEG溶液中，制备出Met@HA-PEG水凝胶。

图：高糖微环境中二甲双胍的释放

结论：该文献释放动力学结果表明，DSPE-PEG2000-PBA参与制备的Met@HA-PEG可以通过响应葡萄糖浓度的变化来调节二甲双胍的用量。与高糖处理组相比，Met@HA-PEG可以保护线粒体免受ROS的影响，从而抑制NLRP3通路的激活，最终增加细胞中细胞外基质（ECM）的合成。Met@HA-PEG可刺激ECM合成，有效促进组织再生。