Reduction Responsive Self-Assembled Nanoparticles Based on Disulfide-Linked Drug-Drug Conjugate with High Drug Loading and Antitumor Efficacy
Reduction Responsive Self-Assembled Nanoparticles Based on Disulfide-Linked Drug-Drug Conjugate with High Drug Loading and Antitumor Efficacy
复制标题
基于二硫键连接的药物-药物缀合物的还原响应自组装纳米粒子，具有高载药量和抗肿瘤功效
DOI：
10.1021/acs.molpharmaceut.5b00631
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发表时间：
2016-01-01
影响因子：
4.9
通讯作者：
Zhang, Qiang
中科院分区：
文献类型：
--
作者：
Song, Qin;Wang, Xing;Zhang, Qiang
大多数抗癌药物溶解性差且无特异性，限制了其临床应用。药物偶联物作为一种前药策略，提供了克服这些缺点的可能性，特别是与纳米技术相结合。药物偶联纳米粒具有载药量高、被动靶向肿瘤等优点。在此，我们制备了基于二硫键连接的阿霉素药物药物缀合物（DOX-SS-DOX）的阿霉素药物药物缀合物纳米粒（DOX-SS-DOX NPs）。动态光散射（DLS）和透射电子显微镜（TEM）表征表明DOX-SS-DOX NP是球形的，具有约89 nm的均匀尺寸分布。DLS和体外释放实验表明DOX-SS-DOX纳米粒具有还原响应活性。体外细胞摄取研究表明，DOX-SS-DOX纳米粒与DOX脂质体相比，可显著提高细胞摄取水平。胞吞机制分析表明DOX-SS-DOX纳米粒通过网格蛋白介导的胞吞途径以能量依赖的方式内化到细胞中。以这种方式，溶酶体中的酰胺酶可以破坏酰胺键以释放游离DOX，这将有助于抗肿瘤活性。DOX-SS-DOX NPs的体外细胞毒性略弱于DOX脂质体，这可能是二硫键缓慢裂解的结果;但在MCF-7荷瘤小鼠中评价的DOX-SS-DOX NPs的抗肿瘤效力被证明高于DOX脂质体。这可能是因为二硫键缓慢裂解产生的持久效应。总之，DOX-SS-DOX纳米粒几乎完全与药物一起制备，为癌症治疗提供了良好的策略。
Most anticancer drugs are poorly soluble and nonspecific, which restricts their clinical application. Drug conjugates, as a prodrug strategy, provide the possibility to overcome these shortcomings, especially combined with nanotechnology. Drug conjugate nanoparticles possess the advantages of high drug loading capacity and passive tumor targeting ability. Here, we prepared doxorubicin drug drug conjugate nanoparticles (DOX-SS-DOX NPs) based on disulfide-linked doxorubicin drug drug conjugate (DOX-SS-DOX). Dynamic light scattering (DLS) and transmission electron microscope (TEM) characterization indicated that DOX-SS-DOX NPs were spherical with a uniform size distribution around 89 run. DLS and in vitro release experiment revealed that DOX-SS-DOX NPs possessed reduction responsive activity. In vitro cellular uptake studies reflected that DOX-SS-DOX NPs could increase the uptake level substantially compared with DOX liposomes. Endocytosis mechanism assay demonstrated that DOX-SS-DOX NPs internalized into cells through a clathrin-mediated endocytosis pathway in an energy-dependent manner. In this manner, the amidase in lysosomes could break the amide bond to release free DOX, which would be helpful to antitumor activity. The in vitro cytotoxicity of DOX-SS-DOX NPs was a bit weaker than that of DOX liposomes, which might be the result of the slow cleavage of the disulfide bridge; but the antitumor efficacy of DOX-SS-DOX NPs evaluated in MCF-7 bearing mice was demonstrated to be higher than that of DOX liposomes. This might be because of the long lasting effect resulting from the slow cleavage of the disulfide bond. In summary, DOX-SS-DOX NPs, prepared nearly totally with drug, provide a good strategy for cancer therapy.