降低膀胱灌注刺激性并增加肿瘤蓄积的表阿霉素前药胶束

The epirubicin prodrug micelles that can reduce bladder perfusion irritation and increase accumulation in tumor

目的制备pH敏感型羟乙基淀粉-表阿霉素(hydroxyethyl starch epirubicin,HES-EPI)亚胺键键合前药胶束,并进行体内外评价。方法采用高碘酸钠氧化法制备醛基化羟乙基淀粉(aldehyded hydroxyethyl starch,HES-CHO),随后在乙酸钠/乙酸缓冲溶液中,与表阿霉素(epirubicin,EPI)发生加成反应,合成以酸敏感亚胺键键合前药HES-EPI。前药进一步自组装形成纳米胶束,并对其粒径、形貌和体外释放行为进行考察。以雌性SD大鼠为动物模型,进行体内刺激性、血浆暴露和组织分布评价。结果HES-EPI前药胶束平均粒径为(124.30±0.3)nm,多分散系数(polydispersity index,PDI)为0.255±0.008,平均电位为(-25.8±2.4)mV,透射电镜(transmission electron microscope,TEM)观察胶束形貌呈类球形,其释放缓慢且具有pH依赖性。组织HE染色切片结果显示与原型药相比前药胶束具有更低刺激性。根据药时曲线计算原型药EPI·HCl组C_(max)为(98.40±4.13)μg·L^(-1),AUC_(0-t)为70.56μg·L^(-1)·h;HES-EPI组C_(max)为(72.27±4.92)μg·L^(-1),AUC_(0-t)为20.09μg·L^(-1)·h,证实了与原型药相比前药胶束具有更低的血浆暴露。荧光成像结果表明药物在肿瘤组织有特异性蓄积。结论本文作者报道了一种基于亚胺键的前药胶束,制备工艺简便,且可通过选择性降低EPI对正常组织的亲和性与通透性的方式实现膀胱灌注过程中的毒性和不良反应降低,改善临床上常见的化学性膀胱炎问题,在膀胱癌的临床治疗中显示出较大的潜力。

Objective To prepare pH-sensitive hydroxyethyl starch-epirubicin(HES-EPI)prodrug micelles conjugated by imine bonds and evaluate its in vitro and in vivo performances.Methods Hydroxyethyl starch was first oxidized by sodium periodate to prepare The aldehyde-based(HES-CHO),followed by an addition reaction with epirubicin(EPI)in sodium acetate/acetic acid buffer solution to synthesize HES-EPI as an acid-sensitive imine bonded prodrug.The micelles were then prepared by self-assemble of prodrug,and its particle size,morphology and in vitro release behavior were further investigated.Female SD rats were used as animal models to evaluate in vivo irritation,plasma exposure and tissue distribution.Results The average particle size of HES-EPI prodrug micelles was(124.30±0.3)nm,the polydispersity index(PDI)was 0.255±0.008,and the average zeta potential was(-25.8±2.4)mV.The prodrug micelles were found with sphere-like morphology by transmission electron microscopy(TEM)and showed a sustained yet pHdependent release.The HE staining results showed that the prodrug micelles exhibited lower tissue irritation than the EPI.And according to the plasma drug concentration-time curves,the C_(max)and AUC_(0-t)of the EPI·HCl were(98.40±4.13)μg·L^(-1)and 70.56μg·L^(-1)·h,respectively.While the C_(max)and AUC_(0-t)of HES-EPI group were(72.27±4.92)μg·L^(-1),and 20.09μg·L^(-1)·h,respectively,indicating a lower plasma exposure of the prodrug micelles.Ex vivo fluorescence imaging results showed a higher drug accumulation in tumor tissues after prodrug micelle instillation.Conclusion In this paper,imide-based prodrug micelles with simple preparation process were reported.It can reduce the toxic and side effects of EPI during bladder instillation by selectively reducing the affinity and permeability of EPI to normal tissues,and lowered the incidence of chemical cystitis commonly accompanied with EPI instillation.These features guaranteed a promise in the clinical treatment of bladder cancer.