National Glycoengineering Research Center, Shandong Key Laboratory of Carbohydrate Chemistry and Glycobiology, NMPA Key Laboratory for Quality Research and Evaluation of Carbohydrate Based Medicine, Shandong University, Qingdao, China.
Santolecan Pharmaceuticals LLC, Jupiter, FL, USA.
Drug Deliv. 2023 Dec;30(1):40-50. doi: 10.1080/10717544.2022.2152133.
Most chemotherapeutic agents are nonspecific distribution and cause systemic toxicities. Polysaccharide-based conjugates are promising strategies to overcome these drawbacks. To this end, two synergistic drugs docetaxel (DTX) and docosahexaenoic acid (DHA) were independently covalently bonded through individual linkers to dextran (100 kDa) to produce a novel dual-drug conjugate dextran-DHA-DTX. The single-drug conjugates dextran-DHA and dextran-DTX were also prepared for comparison. Fluorescent dye Cy7.5-based conjugates dextran-Cy7.5 and dextran-DHA-Cy7.5 were synthesized for cellular uptake study. The dual-drug conjugate dextran-DHA-DTX self-assembled into nanoparticles with the diameter of 102.3 ± 8.3 nm and demonstrated enhanced water solubility and improved pharmacokinetic profiles. Cellular uptake results showed that the dual-drug conjugate entered cells more than the parent DTX by determining the intracellular DTX contents via HPLC/MS analysis and by determining the fluorescent intensity of dextran-Cy7.5 and dextran-DHA-Cy7.5. Importantly, the dual-drug conjugate dextran-DHA-DTX significantly accumulated in tumor tissues and dramatically reduced the DTX concentrations in normal tissues. The dual-drug conjugate completely eradicated all the MCF-7 xenograft tumors without obvious side effects and showed more superior antitumor activity than parent DTX and single-drug conjugate dextran-DTX and dextran-DHA. Both and studies showed that DHA enhanced the antitumor activity of dextran-DTX. The polysaccharide dextran-based dual-drug conjugates may represent an effective way to improve the chemotherapeutic agents.
大多数化疗药物分布不均匀，会导致全身毒性。多糖结合物是克服这些缺点的有前途的策略。为此，两种协同药物多西他赛（DTX）和二十二碳六烯酸（DHA）分别通过各自的连接子与葡聚糖（100 kDa）共价结合，生成一种新型的双重药物结合物葡聚糖-DHA-DTX。还制备了两种单药结合物葡聚糖-DHA 和葡聚糖-DTX 进行比较。合成了荧光染料 Cy7.5 结合物葡聚糖-Cy7.5 和葡聚糖-DHA-Cy7.5 用于细胞摄取研究。双重药物结合物葡聚糖-DHA-DTX 自组装成直径为 102.3 ± 8.3nm 的纳米颗粒，表现出增强的水溶性和改善的药代动力学特征。细胞摄取结果表明，通过 HPLC/MS 分析测定细胞内 DTX 含量和测定葡聚糖-Cy7.5 和葡聚糖-DHA-Cy7.5 的荧光强度，双重药物结合物比亲代 DTX 更多地进入细胞。重要的是，双重药物结合物葡聚糖-DHA-DTX 在肿瘤组织中大量积累，并显著降低正常组织中的 DTX 浓度。双重药物结合物完全消除了所有 MCF-7 异种移植肿瘤，没有明显的副作用，并且比亲代 DTX 和单药结合物葡聚糖-DTX 和葡聚糖-DHA 表现出更优异的抗肿瘤活性。和 研究均表明 DHA 增强了葡聚糖-DTX 的抗肿瘤活性。基于多糖葡聚糖的双重药物结合物可能代表改善化疗药物的有效途径。
