Self-Assembling Doxorubicin-Tocopherol Succinate Prodrug as a New Drug Delivery System: Synthesis, Characterization, and in Vitro and in Vivo Anticancer Activity
Self-Assembling Doxorubicin-Tocopherol Succinate Prodrug as a New Drug Delivery System: Synthesis, Characterization, and in Vitro and in Vivo Anticancer Activity
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DOI：
10.1021/bc400326y
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发表时间：
2014-01-01
影响因子：
4.7
通讯作者：
Preat, Veronique
中科院分区：
文献类型：
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作者：
Duhem, Nicolas;Danhier, Fabienne;Preat, Veronique
自组装前药形成纳米聚集体是提高抗癌药物抗肿瘤疗效、降低抗癌药物毒性的有效途径。为了实现这一目标，将阿霉素通过酰胺键与D-α-生育酚琥珀酸酯化学偶联，得到N-阿霉素-α-D-生育酚琥珀酸酯(N-DOX-TOS)。当D-α-生育酚聚乙二醇2000琥珀酸酯稳定时，前药在水中自组装成250 nm纳米结构。冷冻-透射电子显微镜分析表明，纳米颗粒的形成具有高度有序的片层内部结构。N-DOX-TOS纳米粒子的核磁共振谱表明，N-DOX-TOS位于纳米粒子的核心，而聚乙二醇链和部分生育酚位于冠层。载药量高(34%w/w)，体外释药低。体外生物学评价显示，N-DOX-TOS纳米粒具有显著的抗癌活性和细胞摄取的温度依赖性。在体内，这些纳米粒显示出比游离DOX更强的抗肿瘤效果。N-DOX-TOS纳米粒可能有潜力改进基于DOX的化疗。
Self-assembled prodrugs forming nanoaggregates are a promising approach to enhance the antitumor efficacy and to reduce the toxicity of anticancer drugs. To achieve this goal, doxorubicin was chemically conjugated to D-alpha-tocopherol succinate through an amide bond to form N-doxorubicin-alpha-D-tocopherol succinate (N-DOX-TOS). The prodrug self-assembled in water into 250 nm nanostructures when stabilized with D-alpha-tocopherol poly(ethylene glycol) 2000 succinate. Cryo-TEM analysis revealed the formation of nanoparticles with a highly ordered lamellar inner structure. NMR spectra of the N-DOX-TOS nanoparticles indicated that N-DOX-TOS is located in the core of the nanoparticles while PEG chains and part of the tocopherol are in the corona. High drug loading (34% w/w) and low in vitro drug release were achieved. In vitro biological assessment showed significant anticancer activity and temperature-dependent cellular uptake of N-DOX-TOS nanoparticles. In vivo, these nanoparticles showed a greater antitumor efficacy than free DOX. N-DOX-TOS nanoparticles might have the potential to improve DOX-based chemotherapy.