载亚硝基脲的多功能纳米载体的构建及其评价  

Construction and Evaluation of Multifunctional Nanocarriers Carrying Nitrosourea

作　　者：韩凯硕 王小利[1] 任婷[1] 李多 孙国辉[1] 张娜[1] 赵丽娇[1] 钟儒刚[1] HAN Kai-shuo;WANG Xiao-li;REN Ting;LI Duo;SUN Guo-hui;ZHANG Na;ZHAO Li-jiao;ZHONG Ru-gang(Beijing Key Laboratory of Environmental&Viral Oncology,Faculty of Environment&Life,Beijing University of Technology,Beijing 100124,China)

机构地区：[1]北京工业大学、环境与生命学部、环境与病毒肿瘤学北京市重点实验室,北京100124

出　　处：《化学试剂》2023年第9期19-28,共10页Chemical Reagents

基　　金：北京市百千万人才工程培养项目(2019A16);北京市教委重点实验室项目(PXM2015-014204-500175);国家自然科学基金资助项目(82003599)。

摘　　要：氯乙基亚硝基脲(CENUs)是临床上重要的抗肿瘤烷化剂,但因其水溶性差、毒副作用高以及肿瘤细胞内高表达的O^(6)-烷基鸟嘌呤-DNA烷基转移酶介导的肿瘤细胞耐药性,降低了CENUs的抗癌效果。为了克服上述弊端,合成了一种叶酸修饰抗耐药低氧激活纳米递送系统,用于CENUs的靶向递送。终产物及各中间体的结构经1HNMR、13 CNMR、IR及HRMS确证,使用动态光散射(DLS)、紫外-可见分光光度计(UV-Vis)和透射电子显微镜(TEM)等表征纳米载体的理化性质及形貌,并利用高效液相色谱法(HPLC)测定纳米载体的包封率、载药量及其释药行为。此外,经细胞摄取、细胞毒性和划痕实验评价载药纳米载体的靶向性、低氧响应性和肿瘤细胞抑制能力。结果表明,该纳米载体具有合适的粒径、良好的安全性和优良的载药性能,可实现CENUs的靶向递送和低氧响应释放,能够有效抑制肿瘤细胞的增殖。Chloroethylnitrosoureas(CENUs)are clinically vital antitumor alkylating agents,but the anticancer effect of CENUs is limited due to their poor water solubility,high toxicities and tumor cell resistance mediated by high expression of O^(6)-alkylguanine-DNA alkyltransferase(AGT)in tumor cells.To overcome these drawbacks,this study synthesized a folate-modified anti-drug-resistant hypoxia-activated nano-delivery system for the targeted delivery of CENUs.The chemical structures of the end products and intermediates were confirmed by 1HNMR,13 CNMR,IR and HRMS.The physicochemical properties and morphology of nanocarriers were evaluated by dynamic light scattering(DLS),ultraviolet visible spectrophotometer(UV-Vis),and transmission electron microscope(TEM).The encapsulation efficiency,drug loading and drug release behavior of nanocarriers were also determined by high performance liquid chromatography(HPLC).In addition,cell uptake,cytotoxicity and cell scratch experiments were utilized to evaluate the targeting,hypoxic responsiveness,and tumor cell inhibition of drug-loaded nanocarriers.The results demonstrated that the nanocarrier possesses suitable particle size,favorable safety and excellent drug loading performance,which can achieve targeted delivery and hypoxia responsive release of CENUs for effectively inhibiting the proliferation of tumor cells.

关 键 词：氯乙基亚硝基脲 纳米药物递送系统 耐药性 靶向性 低氧激活 

分 类 号：R914[医药卫生—药物化学]