叶酸修饰角鲨烯化西达本胺前药自组装纳米粒的构建与增强胰腺癌微环境递药的实验研究

The development of folate modified squalene-chidamide prodrug self-assembled nanoparticles to enhance the drug delivery in pancreatic cancer microenvironment

本研究针对化药及中药亲水性小分子抗肿瘤药物难以突破胰腺癌致密间质渗透屏障达到肿瘤组织深部发挥药效的关键问题,将亲脂性分子角鲨烯(squalene,SQ)与亲水性抗肿瘤药物西达本胺(chidamide,CHI)以胰酶响应键连接形成前药分子(SQ-CHI),进一步制备叶酸修饰的前药自组装纳米粒(FA-SQ-CHI NPs)。作者表征了前药分子和纳米粒;研究其体外释放特性与空白载体细胞毒性;比较该前药纳米粒在PSN-1单层细胞和PSN-1/HSPC共培养肿瘤球模型中的药效和渗透过程。结果显示成功构建了SQ-CHI前药分子和FA-SQ-CHI NPs。纳米粒为规则球形,分散良好,粒径为(173.3±1.5)nm,载药量为(59.02±0.8)%,具有胰酶响应释药特性。前药纳米粒可显著增强CHI在PSN-1/HSPC肿瘤球中的渗透和肿瘤细胞杀伤作用。综上,通过构建叶酸修饰的角鲨烯化西达本胺前药自组装纳米粒,可显著增强西达本胺胰腺癌微环境的渗透和抗肿瘤药效,为化药及中药亲水性小分子药物在抗胰腺癌的应用提供新的靶向递药系统构建思路。

This research aimed at the key issue that chemical drugs and Chinese medicine hydrophilic small molecule anti-tumor drugs were difficult to break through the dense interstitial permeability barrier of pancreatic cancer to achieve the key problem of drug efficacy in the deep part of tumor tissue.To solve this problem,the lipophilic molecule squalene(SQ)and the hydrophilic anti-tumor drug chidamide(CHI)were linked by a trypsin responsive bond to form a prodrug(SQ-CHI)and a folic acid modified prodrug self-assembled nanoparticles(FA-SQ-CHI NPs)were further developed.The feature of prodrug molecules and nanoparticles were characterized.The in vitro release characteristics and cytotoxicity of blank vector were investigated.The efficacy and permeability of the prodrug nanoparticles in the PSN-1 monolayer cell and PSN-1/HSPC co-cultured tumor spheroids model was evaluated.The results showed that SQ-CHI prodrug molecules and FA-SQ-CHI NPs were successfully developed.The nanoparticles were regular spherical,well-dispersed,with a particle size of(173.3±1.5)nm,a drug load of(59.02±0.8)%and showed trypsin responsive release ability.The prodrug nanoparticles can significantly enhance the penetration and anti-proliferation effects of CHI in the PSN-1/HSPC tumor spheroids.In conclusion,the construction of folic acid-modified SQ-CHI prodrug self-assembled nanoparticles can significantly enhance the penetration of CHI in the pancreatic cancer microenvironment in vitro.This research would provide a new idea for the construction of targeted drug delivery system for chemical drugs and Chinese medicine hydrophilic small molecule drugs in the application of anti-pancreatic cancer.