Department of Pharmacy, Faculty of Pharmacy, Mahidol University, Ratchathewi, Bangkok 10400, Thailand; Center of Excellence in Innovative Drug Delivery and Nanomedicine, Faculty of Pharmacy, Mahidol University, Ratchathewi, Bangkok, 10400, Thailand.
University of Nottingham, School of Pharmacy, University Park, Nottingham, NG7 2RD, UK.
Colloids Surf B Biointerfaces. 2018 Jul 1;167:115-125. doi: 10.1016/j.colsurfb.2018.03.048. Epub 2018 Mar 28.
Polymer-drug conjugates have been actively developed as potential anticancer drug delivery systems. In this study, we report the first polymer-anticancer drug conjugate with poly(glycerol adipate) (PGA) through the successful conjugation of methotrexate (MTX). MTX-PGA conjugates were controllably and simply fabricated by carbodiimide-mediated coupling reaction with various high molar ratios of MTX. The MTX-PGA conjugate self-assembled into nanoparticles with size dependent on the amount of conjugated MTX and the pH of medium. Change in particle size was attributed to steric hindrance and bulkiness inside the nanoparticle core and dissociation of free functional groups of the drug. The MTX-PGA nanoparticles were physically stable in media with pH range of 5-9 and ionic strength of up to 0.15 M NaCl and further chemically stable against hydrolysis in pH 7.4 medium over 30 days but enzymatically degradable to release unchanged free drug. Although 30%MTX-PGA nanoparticles exhibited only slightly less potency than free MTX in 791T cells in contrast to previously reported human serum albumin-MTX conjugates which had >300 times lower potency than free MTX. However, the MTX nanoparticles showed 7 times higher toxicity to Saos-2 cells than MTX. Together with the enzymic degradation experiments, these results suggest that with a suitable biodegradable polymer a linker moiety is not a necessary component. These easily synthesised PGA drug conjugates lacking a linker moiety could therefore be an effective new pathway for development of polymer drug conjugates.
聚合物-药物偶联物已被积极开发为潜在的抗癌药物递送系统。在这项研究中，我们报告了首例聚（己二酸甘油酯）（PGA）与甲氨蝶呤（MTX）成功偶联的聚合物-抗癌药物偶联物。通过碳二亚胺介导的偶联反应，以各种高摩尔比的 MTX 可控且简单地制备了 MTX-PGA 偶联物。MTX-PGA 偶联物自组装成纳米颗粒，其尺寸取决于共轭 MTX 的量和介质的 pH 值。粒径的变化归因于纳米颗粒核心内的空间位阻和体积庞大以及药物游离官能团的解离。在 pH 值为 5-9 和离子强度高达 0.15 M NaCl 的介质中，MTX-PGA 纳米颗粒物理稳定，并且在 pH 7.4 介质中进一步化学稳定，在 30 天内可抵抗水解，但可酶解以释放不变的游离药物。尽管与先前报道的人血清白蛋白-MTX 缀合物相比，30%MTX-PGA 纳米颗粒在 791T 细胞中的效力仅略低于游离 MTX，但与游离 MTX 的效力相比降低了 300 倍以上。然而，MTX 纳米颗粒对 Saos-2 细胞的毒性比 MTX 高 7 倍。结合酶降解实验，这些结果表明，使用合适的可生物降解聚合物，连接子部分不是必需的。因此，这些易于合成且缺乏连接子部分的 PGA 药物偶联物可能是开发聚合物药物偶联物的有效新途径。
