On-demand drug delivery from temperature-responsive polyurethane membrane

To provide on-demand therapeutics to diseased site where local and intermittent drug delivery was desirable, temperature-responsive polyurethane (TRPU) which enabled rapid, reproducible and tunable on-off switching release of incorporated drugs was successfully prepared. Differential scanning calorimetric analysis revealed that the TRPU synthesized in this study exhibited segmented structure with partially-miscible fixed phase and reversible phase, which favorably imparted the TRPU a physiologically-tolerable switching temperature at 44 degrees C. Positron annihilation lifetime spectroscopy demonstrated that, as the TRPU underwent sharp phase transition-upon heating through 44 degrees C. the free volume size and fraction within the polymeric matrix expanded dramatically. Based on such discontinuous free volume change, the diffusion of incorporated antibiotic (sulfamethoxazole) and anticancer drug (paclitaxel) from TRPU membrane could be switched off below normal physiological temperature (37 degrees C) while switched on by heating to 44 degrees C. resulting in high on-off ratios. In addition, the TRPU membrane could be thermally-switched on and off rapidly, within less than 5 min after temperature variation, and reproducibly, over four cycles of temperature oscillation between 37 degrees C and 44 degrees C. Furthermore, the amount of drug released during each on state was found to be proportional to the duration of heating. In cell culture assays, the TRPU membrane exhibited no cytotoxicity towards C2C12 myoblasts, 3T3 fibroblasts, Me-T mesothelials and J.1774 macrophages. Compared with ordinary biomedical polyurethane elastomer that delivered drugs at almost constant rate regardless of temperature variation, the TRPU prepared in this study showed great potential for developing biomedical implant which could provide temperature-modulated therapeutics to diseased site. (C) 2011 Elsevier Ltd. All rights reserved.

为了向需要局部和间歇性给药的病变部位提供按需治疗药物，成功制备了温度响应型聚氨酯（TRPU），它能够对所负载的药物进行快速、可重复且可调节的开关式释放。差示扫描量热分析表明，本研究中合成的TRPU具有分段结构，包含部分混溶的固定相和可逆相，这使得TRPU在44℃具有生理可耐受的转变温度。正电子湮没寿命谱显示，当TRPU在加热通过44℃时发生急剧的相变，聚合物基质内的自由体积大小和分数急剧增加。基于这种不连续的自由体积变化，所负载的抗生素（磺胺甲恶唑）和抗癌药物（紫杉醇）从TRPU膜中的扩散在正常生理温度（37℃）以下可被关闭，而在加热到44℃时可被开启，从而产生较高的开关比。此外，TRPU膜在温度变化后不到5分钟内即可快速地热开关，并且在37℃和44℃之间经过四个温度振荡周期可重复进行。而且，发现每次开启状态下释放的药物量与加热持续时间成正比。在细胞培养实验中，TRPU膜对C2C12成肌细胞、3T3成纤维细胞、Me - T间皮细胞和J.1774巨噬细胞没有细胞毒性。与普通的生物医用聚氨酯弹性体相比，后者无论温度如何变化几乎都以恒定速率释放药物，而本研究中制备的TRPU在开发能够向病变部位提供温度调节治疗的生物医用植入物方面显示出巨大潜力。（C）2011爱思唯尔有限公司。保留所有权利。