Junyaprasert Varaporn Buraphacheep, Dhanahiranpruk Sirithip, Suksiriworapong Jiraphong, Sripha Kittisak, Moongkarndi Primchanien
Department of Pharmacy, Faculty of Pharmacy, Mahidol University, Rajathevee, Bangkok 10400, Thailand; Center of Excellence in Innovative Drug Delivery and Nanomedicine, Faculty of Pharmacy, Mahidol University, Rajathevee, Bangkok 10400, Thailand.
Department of Pharmacy, Faculty of Pharmacy, Mahidol University, Rajathevee, Bangkok 10400, Thailand.
Colloids Surf B Biointerfaces. 2015 Dec 1;136:383-93. doi: 10.1016/j.colsurfb.2015.09.013. Epub 2015 Sep 10.
Folic acid-conjugated d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS-FOL) decorated methotrexate (MTX)-conjugated nanoparticles were developed for targeted delivery of MTX to folate receptor-expressed tumor cells. The synthesis of TPGS-FOL followed 3-step process. Firstly, the terminal hydroxyl group of TPGS was converted to sulfonyl chloride using mesyl chloride in comparison with nosyl and tosyl chlorides. The highest conversion efficiency and yield were obtained by mesyl chloride due to the formation of higher reactive intermediate in a presence of triethylamine. Secondly, the substitution of sulfonyl group by sodium azide produced considerably high yield with conversion efficiency of over 90%. Lastly, the coupling reaction of azido-substituted TPGS and propargyl folamide by click reaction resulted in 96% conjugation efficiency without polymer degradation. To fabricate the folate receptor-targeted nanoparticles, 10 and 20%mol MTX-conjugated PEGylated poly(ϵ-caprolactone) nanoparticles were decorated with TPGS-FOL. The size and size distribution of MTX-conjugated nanoparticles relatively increased with %MTX. The MTX release from the nanoparticles was accelerated in acidic medium with an increase of %MTX but retarded in physiological pH medium. The decoration of TPGS-FOL onto the nanoparticles slightly enlarged the size and size distribution of the nanoparticles; however, it did not affect the surface charge. The cytotoxicity and cellular uptake of MCF-7 cells demonstrated that 10% MTX-conjugated nanoparticles and FOL-decorated nanoparticles possessed higher toxicity and uptake efficiency than 20% MTX-conjugated nanoparticles and undecorated nanoparticles, respectively. The results indicated that FOL-10% MTX-conjugated nanoparticles exhibited potential targeted delivery of MTX to folate receptor-expressed cancer cells.
开发了叶酸共轭的d-α-生育酚聚乙二醇1000琥珀酸酯（TPGS-FOL）修饰的甲氨蝶呤（MTX）共轭纳米颗粒，用于将MTX靶向递送至表达叶酸受体的肿瘤细胞。TPGS-FOL的合成遵循三步过程。首先，与 nosyl 和 tosyl 氯相比，使用甲磺酰氯将TPGS的末端羟基转化为磺酰氯。由于在三乙胺存在下形成了更高活性的中间体，甲磺酰氯获得了最高的转化效率和产率。其次，用叠氮化钠取代磺酰基产生了相当高的产率，转化效率超过90%。最后，通过点击反应使叠氮基取代的TPGS与炔丙基叶酸酰胺发生偶联反应，共轭效率达到96%，且聚合物未降解。为了制备靶向叶酸受体的纳米颗粒，用TPGS-FOL修饰了10%和20%摩尔的MTX共轭聚乙二醇化聚（ε-己内酯）纳米颗粒。MTX共轭纳米颗粒的尺寸和尺寸分布随MTX%的增加而相对增大。纳米颗粒中MTX的释放在酸性介质中随着MTX%的增加而加速，但在生理pH介质中则延迟。在纳米颗粒上修饰TPGS-FOL会略微增大纳米颗粒的尺寸和尺寸分布；然而，它不影响表面电荷。MCF-7细胞的细胞毒性和细胞摄取表明，10%MTX共轭纳米颗粒和FOL修饰的纳米颗粒分别比20%MTX共轭纳米颗粒和未修饰的纳米颗粒具有更高的毒性和摄取效率。结果表明，FOL-10%MTX共轭纳米颗粒显示出将MTX靶向递送至表达叶酸受体的癌细胞的潜力。
