自组装白蛋白纳米粒作为阿克拉霉素A递送载体

Self-assembled albumin nanoparticles as a nanocarrier for aclacinomycin A

目的本研究旨在通过阿克拉霉素(ACM)共价结合氨基氧乙酸(AOA)产生的活性中间体,以降低ACM毒性和提高靶向药物。方法采用三(2-羧乙基)膦(TCEP)作为二硫键断裂分子,通过分子间的"打开-中间-闭合"开关制备人血清白蛋白(HSA)的自组装纳米粒(Nanoparticle,NPs)。结果核磁共振氢谱(~1H-NMR)分析表明ACM和AOA之间的结合发生在ACM的酮基(^(12)C)位置。HSA纳米粒(NPs-ACM)负载ACM的载药量为7.4%。NPs-ACM的释放与pH相关。与游离ACM相比,NPs-ACM的细胞毒性和心脏毒性降低。体内研究表明,NPs-ACM对荷瘤小鼠靶向性比游离ACM高4倍(P<0.05)。结论纳米粒NPs-ACM前体药物是理想的ACM肿瘤靶向药物载体。

ObjectiveThis study aimed to reduce the cytotoxicity and improve the targeting of aclacinomycin(ACM)by covalently coupling it with amino-oxyacetic acid(AOA)to generate an active intermediate,AOA-ACM.MethodsAOA-ACM was conjugated with self-assembled human serum albumin(HSA)nanoparticles constructed using Tris(2-carboxyethy1)phosphine(TCEP)as disulfide bond breaking molecules.ResultsConjugation between ACM and albumin nanoparticles was found to occur at an ACM ketone site using1H-NMR.The drug loading efficiency of ACM conjugated with HSA nanoparticles(NPs-ACM)was74%(molar ratio=6:1).The release of NPs-ACM was pH dependent.The cytotoxicity and cardiotoxicity of NPs-ACM were reduced compared with the free ACM.Vivo studies indicated that NPs-ACM exhibited fourfold higher tumor targeting capability on S180-tumor-bearing mice compared with the free ACM(P<0.05).ConclusionThe NPs-ACM prodrug is ideal tumor targeting drug carriers for ACM.