壳聚糖微囊化分泌表达血管内皮抑制素的肿瘤靶向共生菌口服治疗结肠癌的研究

Colorectal cancer is a common malignant tumor with high rate of morbidity and mortality in China,and at present, effective treatment lacks for the inoperable colorectal cancer. Angiogenesis inhibitors have been a focus for the therapy of solid tumors, however these drugs, when administerd over a long term, may result in higher toxicity to heart. The side effect of these drugs will be significantly reduced by application of safe, specific and efficient delivery vectors, that will dramatically lower the dose necessary for inhibiting the angiogenesis and "starveing" the tumor cells. This project is aimed to generate a colorectal cancer-targeted symbiotic bacteria which is able to express and secrete recombinant endostain，and subsequently entrap the recombinant bacteria with chitosan to establish a colon-specific delivery system. It is anticipated that the chitosan capsules, when orally administered, will protect and specifically deliver the recombinant bacteria to colon tissues, leading to localized releasing of recombinant endostain in the hypoxic tumor areas. We would also explore the factors affecting the tumor targeting efficiency of this oral delivery system,and assess its inhibitory effect on tumor growth and angiogenesis in tumors with animal modles. The proposed investigation will provide a innovative tool for colorectal cancer therapy.

结/直肠癌是我国高发生、高死亡率的恶性肿瘤之一，严重威胁人类的健康，对于不能手术治疗的患者目前尚缺乏有效的治疗手段。抑制肿瘤血管新生药物一直是实体肿瘤治疗研究的热点，但长期使用具有较大的心脏毒副反应。安全、特异和高效的运送载体将极大降低其副作用，实现在肿瘤局部小剂量给药，达到抑制肿瘤血管新生从而饿死肿瘤的目标。本项目拟构建分泌表达血管内皮抑制素的肿瘤靶向共生菌，并采用壳聚糖微囊结肠靶向递送系统包封基因修饰的共生菌，以保护并靶向递送共生菌到结肠，被释放出的肿瘤靶向共生菌再选择性定位结/直肠癌肿瘤区域，分泌表达内皮抑制素以抑制肿瘤的生长，由此形成靶向口服系统。本研究将进一步探讨影响其靶向结/直肠癌细胞的因素，通过体内实验研究观察其对结/直肠癌的抑制作用及影响因素，为制备出方便、经济、有效且毒副作用低的口服结/直肠癌靶向药物提供理论依据和临床应用基础，它的研制将造福更多的结直肠癌患者。

结/直肠癌是我国高发生、高死亡率的恶性肿瘤之一，对于不能手术治疗的患者目前尚缺乏有效的治疗手段。抑制肿瘤血管新生药物一直是实体肿瘤治疗研究的热点，但长期使用具有较大的心脏毒副反应。安全、特异和高效的运送载体将极大降低其副作用，实现在肿瘤局部小剂量给药，达到抑制肿瘤血管新生从而饿死肿瘤的目标。本项目通过分子克隆技术构建了分泌表达血管内皮抑制素的肿瘤靶向共生菌，体外检测重组的内皮抑制素的生物活性与商品化的内皮抑制素无统计学差异；人脐带内皮细胞系增殖实验显示内皮抑制素的EC50是403 ng/ml；内皮抑制素基因修饰共生菌的体外分泌量约是472ng/ml。采用壳聚糖-海藻酸微囊结肠靶向递送系统包封基因修饰的共生菌，以保护其通过胃酸并靶向递送共生菌到结肠；体外模拟胃酸降解实验显示壳聚糖-海藻酸微囊能有效保护共生菌。体内实验证实微囊化的基因修饰共生菌有效抑制结肠癌肿瘤生长。综上所述，作为新的口服递送系统，壳聚糖-海藻酸微囊化重组共生菌将对结直肠癌的治疗是经济、便捷和有效的。