Liu Jing, Zhao Dujuan, He Wenxiu, Zhang Huiyuan, Li Zhonghao, Luan Yuxia
School of Pharmaceutical Science, Shandong University, 44 West Wenhua Road, Jinan, Shandong Province 250012, PR China.
Key Lab of Colloid & Interface Chemistry, Shandong University, Ministry of Education, 250100, PR China.
J Colloid Interface Sci. 2017 Feb 1;487:239-249. doi: 10.1016/j.jcis.2016.10.041. Epub 2016 Oct 19.
The anti-leukemia effect of cytarabine (Ara-C) is severely restricted by its high hydrophilic properties and rapid plasma degradation. Herein, a novel amphiphilic small molecular prodrug of Ara-C was developed by coupling a short aliphatic chain, hexanoic acid (HA) to 4-NH of the parent drug. Based on the amphiphilic nature, the resulting bioconjugate (HA-Ara) could spontaneously self-assemble into stable spherical nanoassemblies (NAs) with an extremely high drug loading (∼71wt%). Moreover, folate receptor (FR)-targeting NAs with high grafting efficient folic acid - bovine serum albumin (FA-BSA) conjugate immobilized on the surface (NAs/FA-BSA) was prepared. The results of MTT assays on FR-positive K562 cells and FR-negative A549 cells demonstrated higher cytotoxicity of HA-Ara NAs than the native drug. Especially, the IC values revealed that NAs/FA-BSA was 3 and 2-fold effective than non-targeted NAs after 24 and 48h treatment with K562 cells, respectively indicating FR-mediated enhanced anti-tumor efficacy. In vitro cellular uptake, larger accumulation of HA-Ara NAs were observed in comparative with the free FITC and the results further confirmed the selective uptake of NAs/FA-BSA in folate receptor enriched cancer cells. Above all, self-assembled HA-Ara NAs exhibited potential superiority for Ara-C delivery and FA-modified NAs would be an excellent candidate for targeting leukemia therapy.
阿糖胞苷（Ara-C）的抗白血病作用因其高亲水性和快速的血浆降解而受到严重限制。在此，通过将短脂肪链己酸（HA）与母体药物的4-NH偶联，开发了一种新型的两亲性阿糖胞苷小分子前药。基于两亲性，所得生物共轭物（HA-Ara）可自发自组装成稳定的球形纳米组装体（NAs），具有极高的载药量（约71wt%）。此外，制备了表面固定有高接枝效率叶酸-牛血清白蛋白（FA-BSA）共轭物的叶酸受体（FR）靶向纳米组装体（NAs/FA-BSA）。对FR阳性K562细胞和FR阴性A549细胞的MTT分析结果表明，HA-Ara纳米组装体的细胞毒性高于天然药物。特别是，IC值显示，在用K562细胞处理24小时和48小时后，NAs/FA-BSA的有效性分别是非靶向纳米组装体的3倍和2倍，这分别表明FR介导的抗肿瘤疗效增强。在体外细胞摄取方面，与游离FITC相比，观察到HA-Ara纳米组装体有更大的积累，结果进一步证实了NAs/FA-BSA在富含叶酸受体的癌细胞中的选择性摄取。最重要的是，自组装的HA-Ara纳米组装体在阿糖胞苷递送方面表现出潜在优势，而FA修饰的纳米组装体将是靶向白血病治疗的优秀候选物。
