pH响应的负载甲磺酸去铁胺海藻酸钠水凝胶的制备及初步安全性评价

Preparation and preliminary safety evaluation of pH-responsive sodium alginate hydrogels loaded with desferrioxamine mesylate

目的探讨新型p H响应的负载促血管生成药物甲磺酸去铁胺(DFO)的海藻酸钠水凝胶的制备、理化性质,并初步评价其安全性。方法探究氧化型海藻酸钠(OSA)、己二酸二酰肼(ADH)、聚乙二醇(PEG)及DFO浓度对水凝胶制备的影响;采用流变仪和质构仪分别考察水凝胶的流变学性能和机械性能;通过在不同p H的PBS缓冲液中测定DFO的释放程度,考察水凝胶的p H响应性及体外药物释放;采用细胞毒性和溶血率考察其安全性。结果水凝胶的最佳制备条件为OSA质量浓度为75 mg/mL,ADH质量浓度为15 mg/mL,DFO质量浓度为80μg/mL,PEG质量浓度为5 mg/mL。电镜扫描表明海藻酸钠水凝胶均具有密集的网络孔径,且具有良好的自愈合性;水凝胶的储能模量均在(3.0±1.1)kPa之间,适用于人体皮肤;抗疲劳行为实验表明,新型海藻酸钠水凝胶均能够在循环压缩5个周期后恢复到原有状态,具有优异的回弹性能。在弱酸性条件下DFO的释放较快,表明水凝胶具有p H响应性。利用NIH-3T3细胞评价了水凝胶浸出液的细胞毒性,实验结果表明水凝胶在24、48 h基本无细胞毒性。水凝胶的溶血率<5%,符合医用材料的标准。

Objective To investigate the preparation,physicochemical properties and evaluate the preliminary safety of a novel pH-responsive sodium alginate hydrogel loaded with the pro-angiogenic drug desferrioxamine mesylate(DFO).Methods The effects of oxidized sodium alginate(OSA),adipic acid dihydrazide(ADH),polyethylene glycol(PEG) and DFO concentration on the hydrogel preparation were investigated.The rheological properties and mechanical properties of the hydrogels were investigated by rheometer and texturizer,respectively.The pH responsiveness and in vitro drug release of the hydrogels were investigated by measuring the degree of DFO release in PBS buffer of different pH;and the safety of the hydrogels was examined using cytotoxicity and hemolysis rate.Results The optimal preparation conditions for the hydrogels were OSA concentration of 75 mg/mL,ADH concentration of 15 mg/mL,DFO concentration of 80 μg/mL,and PEG concentration of 5 mg/mL.Scanning electron microscopy showed that the sodium alginate hydrogels all had dense network pore size and good self-healing properties.The energy storage moduli of the hydrogels were all between(3.0 ± 1.1) kPa,which were suitable for human skin.The anti-fatigue behavior experiments showed that the new sodium alginate hydrogels were able to return to their original state after 5 cycles of repeated compression,and had excellent resilience performance.The faster release of DFO under weak acidic conditions(pH 4.8) indicated that the hydrogels are pH-responsive.The cytotoxicity of the hydrogel leachate was evaluated using NIH-3T3 cells,and the experimental results showed that the hydrogel was basically noncytotoxic at 24 h and 48 h.The hemolysis rates of the hydrogels were all 5%,which met the standards for medical materials.