新型渗透性水凝胶作为载体用于肿瘤的放射性核素植入治疗  

New permeable hydrogel for tumor radiotherapy in situ

作　　者：黄帆[1] 高阳[1] 张玉民[1] 杨丽军[1] 褚丽萍[1] 刘金剑[1] 

机构地区：[1]中国医学科学院放射医学研究所,天津市放射医学与分子核医学重点实验室,天津300192

出　　处：《国际放射医学核医学杂志》2017年第2期81-87,共7页International Journal of Radiation Medicine and Nuclear Medicine

基　　金：国家自然科学基金（51603231）;中国医学科学院与健康科技创新工程项目（2016-12M-3-022）;天津市自然科学基金（16JCQNJC02500）;“协和青年基金资助”和“中央高校基本科研业务费专项资金资助”（3332016098）;中国医学科学院、北京协和医学院“中央级公益性科研院所基本科研业务费”（2016ZX310079）

摘　　要：目的 设计并合成一类新型的渗透性水凝胶,通过物理作用负载放疗剂,用于肿瘤的植入治疗.方法 通过酯化反应合成聚合物PECT-RGD（其中,PECT为含环醚侧基聚己内酯-聚乙二醇三嵌段共聚物;RGD为含有精氨酸-甘氨酸-天冬氨酸的短肽）,通过酰胺化反应和氯胺T法制备^131I标记的透明质酸,核磁共振氢谱（1H-NMR）对其化学结构进行表征;沉淀离心纯化法对标记的透明质酸进行分离纯化;小瓶翻转法验证凝胶的形成;MTT法研究聚合物材料的细胞毒性;利用放射性小动物活体成像系统研究小鼠体内植入的凝胶的体内稳定性及降解情况;通过抑制肿瘤生长体积和肿瘤组织切片研究^131I@PECT-RGD凝胶的体内抗肿瘤效率.结果 聚合物PECT-RGD没有细胞毒性;在正常生理体温（37℃）下能够形成稳定的凝胶,并且可以在体内发生自降解;与PBS组相比,注射131I@PECT-RGD凝胶组和^131I@PECT凝胶组均呈现较高的抗肿瘤效率,与PBS组比较差异有统计学意义（F=71.968,P〈0.05）;^131I@PECT-RGD凝胶组与^131I@PECT凝胶组比较,抗肿瘤效率之间的差异也具有统计学意义（t=-7.276,P〈0.05）;3组小鼠体重差异无统计学意义（F=3.878,P〉0.05）;HE染色结果显示,注射PBS组的肿瘤组织仅出现小部分坏死,注射^131I@PECT凝胶组的肿瘤组织大部分坏死,注射^131I@PECT-RGD凝胶组的肿瘤组织基本坏死.结论 ^131I@PECT-RGD凝胶能够原位注射到肿瘤组织,具有良好的生物相容性、自降解性和抗肿瘤效果,是一种非常有应用前景的肿瘤局部放疗方法.Objective To design and synthesize a novel permeable hydrogel loaded with a radiation agent for the implantation radiotherapy of tumors.Methods The polymer PECT-RGD [PECT：poly（ε-caprolactone-co-1,4,8-trioxa [4.6]spiro-9-undecanone）-poly（ethylene glycol）-poly（ε-caprolactone-co1,4,8-trioxa [4.6]spiro-9-undecanone）;RGD：Arg-Gly-Asp] was synthesized by esterification reaction,and an ^131I-labeled hyaluronic acid was prepared by amidation reaction and chloramine-T method.The chemical structure of them was characterized by ^1H-NMR,and the ^131I-labeled hyaluronic acid was isolated and purified by precipitation and centrifugation.Hydrogel formation was verified by vial flipping experiment,and the cytotoxicity of the polymer materials was evaluated by MTT assay.The in vivo stability and degradation of the injected hydrogel were studied using a radioactive small animal live imaging system.The in vivo antitumor effect of the ^131I@PECT-RGD hydrogel was investigated by inhibiting tumor growth volume and tumor tissue section.Results The polymer PECT-RGD was non-cytotoxic and could form a stable hydrogel under the normal physiological temperature（37℃）.This hydrogel is capable of selfdegradation in vivo.Compared with the PBS group,the 131I@PECT-RGD hydrogel and the ^131I@PECT gel showed significantly higher anti-tumor efficiency （P〈0.05,F=71.968）.A significant difference in anti-tumor efficiency was found between the ^131I@PECT and ^131I@PECT-RGD hydrogels （P〈0.05,t=7.276）.No significant difference in body weight was found among the three groups （P〉0.05,F=3.878）.HE staining showed that only a small part of the tumor tissue was necrotic in the PBS group,whereas a large part of the tumor tissue was necrotic in the ^131I@PECT group;the tumor tissue of the ^131I@PECT-RGD group was generally necrotic.Conclusions The ^131I@PECT-RGD hydrogel could be injected into tumor tissue in situ and display great biocompatibility,self-degradation ability,and anti-tumor activity.Thus,this hydrogel has pot

关 键 词：肿瘤 水凝胶 放射性同位素 近距离放射疗法 

分 类 号：R730.5[医药卫生—肿瘤]