ABSTRACT

We reports a novel thermally enhanced drug release system synthesized via a dynamic Diels-Alder (DA) reaction to develop chemotherapy for pancreatic cancer. The anticancer prodrug was designed by tethering gemcitabine (GEM) to poly(furfuryl methacrylate) (PFMA) via N-(3-maleimidopropionyloxy)succinimide as a linker by DA reaction (PFMA-L-GEM). The conversion rate of the DA reaction was found to be approximately 60% at room temperature for 120 h. The reversible deconstruction of the DA covalent bond in retro Diels-Alder (rDA) reaction was confirmed by proton nuclear magnetic resonance, and the reaction was significantly accelerated at 90 °C. A PFMA-LGEM film containing magnetic nanoparticles (MNPs) was prepared for thermally enhanced release of the drug via the rDA reaction. Drug release was initiated by heating MNPs by alternating magnetic field. This enables local heating within the film above the rDA reaction temperature while maintaining a constant surrounding medium temperature. The MNPs/PFMA-L-GEM film decreased the viability of pancreatic cancer cells by 49% over 24 h. Our results suggest that DA/rDA-based thermally enhanced drug release systems can serve as a local drug release platform and deliver the target drug within locally heated tissue, thereby improving the therapeutic efficiency and overcoming the side effects of conventional drugs used to treat pancreatic cancer.

摘要

我们报告了一种通过动态狄尔斯-阿尔德 (DA) 反应合成的新型热增强药物释放系统，以开发胰腺癌的化学疗法。抗癌前药是通过将吉西他滨 (GEM) 与聚甲基丙烯酸糠酯 (PFMA) 经由N-（3-马来酰亚胺基丙酰氧基）琥珀酰亚胺作为 DA 反应的接头（PFMA-L-GEM）。发现 DA 反应的转化率在室温下 120 小时约为 60%。质子核磁共振证实了逆狄尔斯-阿尔德（rDA）反应中DA共价键的可逆解构，反应在90°C时显着加速。制备了含有磁性纳米粒子 (MNP) 的 PFMA-LGEM 膜，用于通过 rDA 反应热促进药物释放。通过交变磁场加热 MNP 启动药物释放。这使得膜内局部加热高于 rDA 反应温度，同时保持恒定的周围介质温度。MNPs/PFMA-L-GEM 薄膜在 24 小时内将胰腺癌细胞的活力降低了 49%。