主动靶向双药纳米纤维递药体系的放疗协同增敏效果评价及机制研究

胰腺癌细胞由于缺乏精氨酸合成的关键酶导致对精氨酸严重依赖，若是给予外源性的精氨酸脱亚胺酶（ADI）来降解精氨酸则可以有效的杀伤肿瘤细胞。现较为公认的放疗抵抗的机制为放疗会导致NF-kB通路的激活从而增强肿瘤细胞的抗凋亡能力。同时我们前期证实ADI与姜黄素均能够有效增强放疗对于胰腺癌细胞的杀伤效果，且两种药物均可以通过抑制NF-kB通路的活化来产生协同放疗增敏效果。而为了将两种药物的协同放疗增敏效应最大化同时克服传统纳米递药体系的缺陷，我们首先采用二硫键（ss）连接具有纳米自组装能力的二苯基二肽（FFE）以及具有肿瘤间质穿透能力的ERGD小肽得到中间体FFE-ss-ERGD。随后将其与姜黄素（Cur）进行共价结合得到最终载体Cur-FFE-ss-ERGD。采用该载体构建负载ADI和Cur的主动靶向双药纳米载药纤维，在体内外胰腺癌模型上考察其基于“NF-kB通路抑制”的协同放疗增敏效果。

Pancreatic cancer cells are reliable to arginine due to the lack of arginosuccinate synthase. Arginie deiminase can effectively kill cancer cells through degradation of the necessary arginine. Recently it is proved that one of the most important mechanisms underlying the resistance to radiotherapy by cancer cells is the activation of NF-kB pathway, which consequently renders cells much more stronger anti-apoptosis ability. In our preliminary study, both ADI and curcumin (Cur) could promote the apoptosis of cancer cells and the combination of the two drugs generate synergistic radiosensitization effect through inhibiting the activation of NF-kB pathway. To achieve the optimal effect of the synergism and overcome the defects of traditional nano-drug delivery system, we link FFE and ERGD with disulfide bond (ss) and then link FFE-ss-ERGD with Curcumin with chemical bond. We construct ADI and Cur co-loaded nanofibers with Cur-FFE-ss-ERGD as drug carriers. We evaluate the in vitro and in vivo antitumor effects of ADI and Cur and try to elucidate the possible mechanism of the synergistic radiosensitization effect.