缺乏粘膜粘附特性是用于粘膜施用的基于泊洛沙姆407(F127)的原位水凝胶的主要缺点。本研究的目的是基于氨基官能化的泊洛沙姆构建一种用于阴道给药的新型粘膜粘附和热敏原位水凝胶药物递送系统。首先,合成了氨基官能化的泊洛沙姆407(F127-NH2),并对其胶束化行为和与粘蛋白的相互作用进行了表征。然后以醋酸棉酚(AG)为模型药,基于AG负载的F127-NH2的原位水凝胶(NFG)在流变学方面进行了评估,药物释放,离体阴道粘膜粘连,对健康雌性小鼠进行阴道给药后的体内阴道内滞留和局部刺激。结果表明,F127-NH2能够形成具有持续药物释放性质的热敏原位水凝胶。带正电荷的F127-NH2和带负电荷的粘蛋白之间的相互作用通过粘蛋白颗粒的粒径和ζ电位的变化以及由粘蛋白引起的NFG复数模量的增加来揭示。离体和体内荧光成像以及对小鼠阴道灌洗中剩余的AG量的定量分析都证明了比未修饰的基于F127的原位水凝胶更大的NFG阴道内滞留。总之,氨基官能化赋予泊洛沙姆407有价值的粘膜粘附特性。
Lack of mucoadhesive properties is the major drawback to poloxamer 407 (F127)-based in situ hydrogels for mucosal administration. The objective of the present study was to construct a novel mucoadhesive and thermosensitive in situ hydrogel drug delivery system based on an amino-functionalized poloxamer for vaginal administration. First, amino-functionalized poloxamer 407 (F127-NH2) was synthesized and characterized with respect to its micellization behavior and interaction with mucin. Then using acetate gossypol (AG) as model drug, AG-loaded F127-NH2-based in situ hydrogels (NFGs) were evaluated with respect to rheology, drug release, ex vivo vaginal mucosal adhesion, in vivo intravaginal retention and local irritation after vaginal administration to healthy female mice. The results show that F127-NH2 is capable of forming a thermosensitive in situ hydrogel with sustained drug release properties. An interaction between positively charged F127-NH2 and negatively charged mucin was revealed by changes in the particle size and zeta potential of mucin particles as well as an increase in the complex modulus of NFG caused by mucin. Ex vivo and in vivo fluorescence imaging and quantitative analysis of the amount of AG remaining in mouse vaginal lavage all demonstrated greater intravaginal retention of NFG than that of an unmodified F127-based in situ hydrogel. In conclusion, amino group functionalization confers valuable mucoadhesive properties on poloxamer 407.