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pH- and temperature-responsive hydrogels for delivery of angiogenic growth factors.

机译：pH和温度响应水凝胶，用于输送血管生成生长因子。

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摘要

Therapeutic angiogenesis, or the delivery of angiogenic growth factors to promote revascularization, is a promising approach to treat ischemic heart disease. However, improved drug delivery systems (DDSs) are needed to provide effective therapy. Stimuli-responsive hydrogels can be designed take advantage of the low pH environment of ischemic myocardium (pH 6--7). In particular, polymers that are soluble at pH 7.4 and 37°C but form physical gels under conditions of intermediate acidity (pH 6--7) and 37°C could facilitate spatio-temporal control of angiogenic growth factor delivery and improve the efficacy of therapeutic angiogenesis methods.;The pH- and temperature-responsive random copolymer, poly(N-isopropylacrylamide-co-propylacrylic acid) (p[NIPAAm-co-PAA]), was synthesized by reversible addition fragmentation chain transfer polymerization. Viscoelastic properties of this material as functions of pH, temperature, and composition were quantified by rheometry. At physiologic pH (7.4) and 5 w/v %, the polymer did not form gels, but rather remained soluble at temperatures as high as 50°C. At lower pH values (pH5.5) the polymer was a liquid at 20°C but exhibited a sol-gel phase transformation with increasing temperature and existed as a gel at 37°C. Incorporation of the hydrophobic monomer, butyl acrylate (BA), into the random copolymer raised the pH of gel formation to greater than 6.0 at 37°C. Drug loading studies demonstrated that p(NIPAAm-co-PAA) hydrogels are able to provide sustained, pH-dependent release of vascular endothelial growth factor over a period of at least three weeks. P(NIPAAm-co-PAA-co-BA) was used to deliver basic fibroblast growth factor (bFGF) via injection into infarcted rat myocardium. Following 4 weeks of treatment in vivo, there was a 33% increase in capillary density in rats treated with polymer+bFGF compared to untreated saline control rats (p0.001). Treatment with polymer+bFGF for 4 weeks resulted in a 2-fold improvement in relative blood flow to the infarct region compared to day 0 (p0.05). By responding to local changes in pH and temperature in an animal model of ischemia, this DDS was able to provide sustained, local delivery of bFGF and achieve a therapeutic response. Also, this hydrogel could be used for drug delivery to other regions of local acidosis as found in wound healing or tumors.
机译：治疗性血管生成或血管生成生长因子的传递可促进血运重建，是治疗缺血性心脏病的一种有前途的方法。然而，需要改进的药物递送系统（DDS）来提供有效的治疗。可以设计刺激性水凝胶，以利用缺血心肌的低pH环境（pH 6--7）。特别是，在pH 7.4和37°C时可溶但在中等酸度（pH 6--7）和37°C的条件下形成物理凝胶的聚合物可以促进时空控制血管生成生长因子的输送并提高药物的疗效。通过可逆的加成断裂链转移聚合反应合成了pH和温度响应型无规共聚物聚（N-异丙基丙烯酰胺-共-丙基丙烯酸）（p [NIPAAm-co-PAA]）。该材料的粘弹性是pH，温度和组成的函数，通过流变法定量。在生理pH（7.4）和5 w / v％时，聚合物不会形成凝胶，而是在高达50°C的温度下仍可溶。在较低的pH值（pH <5.5）下，聚合物在20°C下为液体，但随着温度的升高呈现出溶胶-凝胶相变，并在37°C下以凝胶形式存在。将疏水性单体丙烯酸丁酯（BA）掺入无规共聚物中后，在37°C下，凝胶形成的pH值升至6.0以上。载药研究表明，p（NIPAAm-co-PAA）水凝胶能够在至少三周的时间内持续，pH依赖地释放血管内皮生长因子。 P（NIPAAm-co-PAA-co-BA）用于通过注射入梗死大鼠心肌来递送碱性成纤维细胞生长因子（bFGF）。在体内治疗4周后，与未治疗的生理盐水对照组相比，用聚合物+ bFGF治疗的大鼠的毛细血管密度增加了33％（p <0.001）。与第0天相比，用聚合物+ bFGF治疗4周导致到达梗塞区域的相对血流增加了2倍（p <0.05）。通过响应局部缺血动物模型中pH和温度的局部变化，该DDS能够提供持续的bFGF局部递送并实现治疗反应。同样，这种水凝胶可用于将药物递送至伤口愈合或肿瘤中发现的局部酸中毒的其他区域。

著录项

  • 作者

    Garbern, Jessica Chow.;

  • 作者单位

    University of Washington.;

  • 授予单位 University of Washington.;
  • 学科 Chemistry Polymer.;Health Sciences Medicine and Surgery.;Engineering Biomedical.
  • 学位 Ph.D.
  • 年度 2009
  • 页码 214 p.
  • 总页数 214
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 高分子化学（高聚物）;生物医学工程;
  • 关键词

  • 入库时间 2022-08-17 11:38:26

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