Department of Biomedical Engineering, University of Minnesota, 7-105 Hasselmo Hall, 312 Church Street Southeast, Minneapolis, Minnesota 55455, USA.
Biomacromolecules. 2009 Apr 13;10(4):722-7. doi: 10.1021/bm9000475.
A new, convenient pathway is developed to synthesize highly hydrolytically labile poly(ortho ester amide) (POEA) copolymers that overcomes some of the major weaknesses of the traditional methods of synthesizing poly(ortho esters) and their derivatives. A diamine monomer containing a built-in, stabilized ortho ester group was synthesized and was used for polycondensation with diacid esters, giving rise to a series of POEA copolymers with unique stimuli-responsive properties. The POEA undergoes temperature-responsive, reversible sol-gel phase transition in water. Phase diagrams of the POEA/H(2)O mixture reveal the concentration-dependent existence of different phases, including hydrogel and opaque or clear solution. Such behavior may be attributed to the temperature-dependent hydrogen-bonding involving the amide groups in the POEA backbone and hydrophobic interactions between POEA chains, and it is tunable by selecting diacid monomers with different chemical structures. The kinetics of POEA mass loss in physiological aqueous buffers and release of a model macromolecular drug, fluorescently labeled dextran, are nearly zero-order, suggesting predominantly surface-restricted polymer erosion. The rates of polymer erosion and drug release are much faster at pH 5.0 than pH 7.4. No cytotoxicity was found for the polymer extracts and the polymer degradation products at concentrations as high as 1 mg/mL. The normal morphology of fibroblasts cultured directly in contact with POEA films was not altered. These novel acid-labile temperature-responsive POEA copolymers may be potentially useful for a wide range of biomedical applications such as minimal invasive delivery of controlled-release drug formulations that respond to biological temperature and acidic-pH environments in cells and tissues.
开发了一种新的、方便的途径来合成高度可水解的聚（原酸酯酰胺）（POEA）共聚物，该途径克服了传统合成聚（原酸酯）及其衍生物方法的一些主要缺点。合成了一种含有内置稳定原酸酯基团的二胺单体，并将其与二酸酯进行缩聚，得到了一系列具有独特刺激响应特性的 POEA 共聚物。POEA 在水中发生温度响应、可逆溶胶-凝胶相转变。POEA/H(2)O 混合物的相图揭示了不同相的浓度依赖性存在，包括水凝胶和不透明或透明溶液。这种行为可能归因于 POEA 主链上酰胺基团的温度依赖性氢键和 POEA 链之间的疏水相互作用，通过选择具有不同化学结构的二酸单体可以对其进行调节。POEA 在生理水性缓冲液中的质量损失和模型大分子药物荧光标记葡聚糖的释放的动力学几乎是零级的，这表明主要是表面受限的聚合物侵蚀。在 pH 5.0 时，聚合物侵蚀和药物释放的速率比 pH 7.4 时快得多。在高达 1 mg/mL 的浓度下，聚合物提取物和聚合物降解产物没有发现细胞毒性。直接与 POEA 薄膜接触培养的成纤维细胞的正常形态没有改变。这些新型的酸敏感温度响应 POEA 共聚物可能在广泛的生物医学应用中具有潜在的用途，例如对生物温度和细胞和组织中的酸性 pH 环境做出响应的控释药物制剂的微创递送。
