Novel reduction‐sensitive micellar nanoparticles assembled from Rituximab–doxorubicin conjugates as smart and intuitive drug delivery systems for the treatment of non‐Hodgkin's lymphoma
Novel reduction‐sensitive micellar nanoparticles assembled from Rituximab–doxorubicin conjugates as smart and intuitive drug delivery systems for the treatment of non‐Hodgkin's lymphoma
复制标题
DOI：
10.1111/cbdd.13010
复制
发表时间：
2017-11
影响因子：
3
通讯作者：
Huabin Yin;T. Meng;Ling Shu;Min Mao;Lei Zhou;Haiyan Chen;D. Song
中科院分区：
文献类型：
--
作者：
Huabin Yin;T. Meng;Ling Shu;Min Mao;Lei Zhou;Haiyan Chen;D. Song
在这项研究中，一种新型的还原敏感药物递送系统，即利妥昔单抗-阿霉素（RTX-DOX）胶束纳米颗粒（RDMN），专门设计用于在非霍奇金淋巴瘤（NHL）细胞中靶向递送和释放DOX。 RDMN是通过自组装两亲性RTX-DOX缀合物（RDC）来制造的，该缀合物是通过还原响应接头3-（2-吡啶基二硫代）丙酰肼将RTX（抗CD20单克隆抗体）的亲水性Fab片段和疏水性DOX缀合而合成的 （PDPH）。通过动态光散射和透射电子显微镜对 RDMN 进行了表征，两者均显示尺寸约为 94.1 ± 14.5 nm，且尺寸分布均匀。由于 PDPH 连接体中二硫键的断裂，在 2.5 mm 1,4-二硫苏糖醇存在的情况下观察到了多聚复合物解离，表现为 DOX 释放速率加快和粒径增大。针对人 NHL 细胞系 JeKo-1 的体外转染试验显示，与 RDC 和游离 RTX/DOX 相比，RDMN 的摄取显着增加。体内和离体实验均表明 RDMN 在所有实验组中显示出最高的治疗效果。这些结果表明该RDMN可能是一种潜在的、安全的、高效的药物递送载体，值得在临床上进一步研究。
In this study, a novel reduction‐sensitive drug delivery system, the rituximab–doxorubicin (RTX‐DOX) micellar nanoparticle (RDMN), was specially designed for targeted delivery and release of DOX in non‐Hodgkin's lymphoma (NHL) cells. The RDMN was fabricated by self‐assembling of amphiphilic RTX‐DOX conjugates (RDCs), which were synthesized by conjugating the hydrophilic Fab fragments of RTX (an anti‐CD20 monoclonal antibody) and hydrophobic DOXs by a reduction‐responsive linker, 3‐(2‐Pyridyldithio) propionyl hydrazide (PDPH). The RDMNs were characterized via dynamic light scattering and transmission electron microscopy, both showed the sizes of approximately 94.1 ± 14.5 nm with a uniform size distribution. Polyplex dissociation, which was indicated by accelerated DOX release rate and increased particle size, was observed in the presence of 2.5 mm 1,4‐dithiothreitol due to the cleavage of disulfide bonds in PDPH linkers. In vitro transfection assays against human NHL cell line, JeKo‐1, showed significantly increased uptake for RDMNs, as compared to RDCs and free RTX/DOX. Both in and ex vivo experiments demonstrated that RDMNs showed the highest therapeutic effect among all the experimental groups. These results suggested that this RDMN could be a potential, safe and efficient drug delivery vector, which deserves further investigation in the clinic.