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Shape of Nanoparticles as a Design Parameter to Improve Docetaxel Antitumor Efficacy
Bioconjugate Chemistry ( IF 4.0 ) Pub Date : 2018-02-09 00:00:00 , DOI: 10.1021/acs.bioconjchem.8b00059
Yifei Guo 1 , Shuang Zhao 1, 2 , Hanhong Qiu 1 , Ting Wang 1 , Yanna Zhao 1, 3 , Meihua Han 1 , Zhengqi Dong 1 , Xiangtao Wang 1
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It was reported that the shape of nanocarriers played an important role in achieving a better therapeutic effect. To optimize the morphology and enhance the antitumor efficacy, in this study based on the amphiphilic PAMAM-b-OEG codendrimer (POD), docetaxel-loaded spherical and flake-like nanoparticles (DTX nanospheres and nanosheets) were prepared via an antisolvent precipitation method with similar particle size, surface charge, stability, and release profiles. The feed weight ratio of DTX/POD and the branched structure of OEG dendron were suggested to influence the shapes of the self-assembled nanostructures. As expected, DTX nanospheres and nanosheets exhibited strong shape-dependent cellular internalization efficiency and antitumor activity. The clathrin-mediated endocytosis and macropincytosis-dependent endocytosis were proven to be the main uptake mechanism for DTX nanospheres, while it was clathrin-mediated endocytosis for DTX nanosheets. More importantly, DTX nanosheets presented obviously superior antitumor efficacy over nanospheres, the tumor inhibition rate was increased 2-fold in vitro and 1.3-fold in vivo. An approximately 2-fold increase in pharmacokinetic parameter (AUC, MRT, and T1/2) and tumor accumulation were observed in the DTX nanosheets group. These results suggested that the particle shape played a key role in influencing cellular uptake behavior, pharmacokinetics, biodistribution, and antitumor activity; the shape of drug-loaded nanoparticles should be considered in the design of a new generation of nanoscale drug delivery systems for better therapeutic efficacy of anticancer drug.

中文翻译:

纳米颗粒的形状作为提高多西他赛抗肿瘤功效的设计参数

据报道,纳米载体的形状在实现更好的治疗效果中起着重要作用。为了优化形态并增强抗肿瘤功效,本研究基于两亲性PAMAM- b -OEG共混物(POD),通过抗溶剂沉淀法制备了多西他赛负载的球形和片状纳米颗粒(DTX纳米球和纳米片),相似的粒径,表面电荷,稳定性和释放曲线。DTX / POD的进料重量比提示OEG树枝状分子的分支结构会影响自组装纳米结构的形状。如预期的那样,DTX纳米球和纳米片表现出强大的形状依赖性细胞内化效率和抗肿瘤活性。网格蛋白介导的内吞作用和依赖大粒胞吞作用的内吞作用被证明是DTX纳米球的主要摄取机制,而网格蛋白介导的是DTX纳米片的内吞作用。更重要的是,DTX纳米片表现出明显优于纳米球的抗肿瘤功效,其体外抑瘤率提高了2倍体内抑瘤率则提高了1.3倍。药代动力学参数(AUC,MRT和T 1/2大约增加2倍))和DTX纳米片组中观察到肿瘤积累。这些结果表明,颗粒形状在影响细胞摄取行为,药代动力学,生物分布和抗肿瘤活性中起着关键作用。在设计新一代纳米级药物输送系统时,应考虑载药纳米颗粒的形状,以提高抗癌药物的治疗效果。
更新日期:2018-02-09
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