| 李 宁,宁 敏,宛新建,刘坚华,何伟娜.原位可注射壳聚糖基温敏水凝胶的制备及其在预防ESD术后食管狭窄中分阶段释药应用研究[J].,2023,(1):1-8 |
| 原位可注射壳聚糖基温敏水凝胶的制备及其在预防ESD术后食管狭窄中分阶段释药应用研究 |
| In Situ Forming Injectable Hydrogel for Phased Dosing in Preventing Post-ESD Esophageal Stricture |
| 投稿时间：2022-05-23 修订日期：2022-06-18 |
| DOI：10.13241/j.cnki.pmb.2023.01.001 |
| 中文关键词: 内镜黏膜下剥离术 食管狭窄 壳聚糖水凝胶 原位注射 温敏凝胶 分段释药 |
| 英文关键词: ESD Esophageal stricture Chitosan hydrogel in situ injection Thermosensitive gel Phased dosing |
| 基金项目:国家自然科学基金项目（21504104）；上海市卫健委"优青计划"（2017YQ080）；上海市教委"晨光项目"（16GC14） |
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| 中文摘要: |
| 摘要 目的：构建一种可以分阶段释放药物的原位可注射水凝胶，通过直接注射在ESD（Endoscopic Submucosal Dissection，内镜黏膜下剥离术）术后伤口处，形成水凝胶敷料，起到保护伤口的作用。同时凝胶中的两种药物通过分阶段释放的方式，更好地促进伤口的无瘢痕愈合，为ESD术后食管狭窄的预防提供一种新的参考方案。方法：在壳聚糖/β-甘油磷酸钠（CS/β-GP）温敏水凝胶的体系中加入聚多巴胺（PDA），制备壳聚糖/β-甘油磷酸钠/聚多巴胺（CS/?β-GP/PDA）水凝胶。通过在载药水凝胶中加入聚乙二醇-聚乳酸-羟基乙酸（PEG-PLGA）纳米载药微粒制备CS/β-GP/PDA/NPs双载药水凝胶，通过两种载药体系的复合，实现药物的分阶段释放。通过流变学实验测定CS/β-GP、CS/β-GP/PDA、CS/β-GP/PDA/NPs凝胶体系的相转变温度以及凝胶强度。通过高效液相色谱法检测CS/β-GP/PDA/NPs水凝胶中两种药物的释放动力学特征。通过CCK-8细胞增殖实验评价CS/β-GP/PDA、CS/β-GP/PDA/NPs温敏水凝胶的生物相容性。在体外猪食管中，模拟ESD术后创口，通过内镜辅助将水凝胶母液注射在伤口处，并通过内镜观察水凝胶的凝胶状态。结果：得到了粘附性显著增强的壳聚糖/β-甘油磷酸钠/聚多巴胺（CS/β-GP/PDA）凝胶体系。流变学实验证明聚多巴胺（PDA）的加入可以显著降低水凝胶的凝胶温度，缩短原位成胶时间。CCK-8实验显示CS/β-GP/PDA、CS/β-GP/PDA/NPs凝胶体系无潜在的细胞毒性。在体外猪食管模拟实验中，将其凝胶母液注射在伤口处后，可原位形成凝胶，且凝胶贴合伤口，具有较强的粘附性。通过体外释药速率测定，验证了CS/β-GP/PDA/NPs水凝胶中所载两种药物释放速率存在明显差异，可实现药物的分阶段释放。结论：设计的CS/β-GP/PDA/NPs凝胶体系适用于ESD术后的伤口修复，并能够实现分阶段释药，对于预防ESD术后食管狭窄具有潜在的应用价值。 |
| 英文摘要: |
| ABSTRACT Objective: To construct an insitu injectable Chitosan-based hydrogel for phased dosing, of which the sol solution is injected directly into the wound after ESD (Endoscopic Submucosal Dissection) surgery to form a hydrogel dressing in situ. After introducing drug-loaded nanoparticles into the hydrogel dressing, the dual drug-loaded hydrogel can promote the scar-free healing of wounds through different release kinetics of the drugs contained in the gel and nanoparticles, which will be a good solution for preventing post-ESD esophageal stricture. Methods: Polydopamine (PDA) is added to chitosan/sodium glycerophosphate (CS/β-GP) thermosensitive hydrogel to prepare chitosan/sodium glycerophosphate/polydopamine (CS/β-GP/PDA) hydrogel. The CS/β-GP/PDA/NPs dual drug-loaded hydrogel was prepared by adding drug-loaded polyethylene glycol-poly lactic acid-co-glycolic acid (PEG-PLGA) nanoparticles to the drug-loaded hydrogel, and the staged release of the drugs was achieved through the combination of the two drug carrier systems. The phase transition temperature and rheological properties of CS/β-GP, CS/β-GP/PDA, CS/β-GP/PDA/NPs gels were determined by rheological tests. The release kinetics of the two drugs in CS/β-GP/PDA/NPs hydrogels was detected by high performance liquid chromatography (HPLC). The biocompatibility of CS/β-GP/PDA, CS/β-GP/PDA/NPs gels was evaluated by CCK-8 cell proliferation experiments. In the porcine esophagus in vitro, the wound that would generate after ESD was simulated. The sol solution was injected into the wound with the aid of endoscopy, and the state of the hydrogel was observed through an endoscope. Results: A chitosan/β-sodium glycerophosphate/polydopamine (CS/β-GP/PDA) gel with significantly enhanced adhesion was prepared. Rheological experiments proved that the addition of PDA could significantly reduce the gel temperature of the hydrogel and shorten the in situ gelling time. CCK-8 experiments showed that CS/β-GP/PDA and CS/β-GP/PDA/NPs gel systems both exhibit minimal cytotoxicity. In the porcine esophagus simulation experiment in vitro, after the sol was injected into the wound, the gel could be formed in situ, and the gel adhered to the wound strongly. Through measuring the drug release rate, it was verified that the release rate of the two drugs contained in the CS/β-GP/PDA/NPs hydrogel was significantly different, suggesting that the phased dosing could be achieved. Conclusion: The designed CS/β-GP/PDA/NPs gel system is suitable for post-ESD wound repair, and could achieve phased dosing, revealing its potential for preventing post-ESD esophageal stricture. |
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