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, 266237, China.
Santolecan Pharmaceuticals LLC, 1261 Islamorada Drive, Jupiter, FL, 33458, USA.
Eur J Med Chem. 2022 Oct 5;240:114567. doi: 10.1016/j.ejmech.2022.114567. Epub 2022 Jun 26.
In this study, a novel carboxymethyl dextran (CMD)-based dual drug delivery system that delivering two water insoluble drugs to tumor sites was developed and evaluated for anticancer activities. Paclitaxel (PTX) and docosahexaenoic acid (DHA) were covalently coupled with CMD to generate CMD-DHA-PTX conjugate S and conjugate L with different linkers containing amino acids Gly-Gly or Lys-Gly-Gly, respectively. Both conjugates possessed high PTX loading contents and enhanced water solubility, as well as the ability of being self-assembled into nanoparticles with the nanoparticle size ranged from 88.7 nm to 94.7 nm. These two conjugates released free PTX continuously in plasma and cancer cells. The conjugate S exhibited improved pharmacokinetic parameters and higher distribution extent in tumor sites than the parent PTX, Abraxane and the conjugate L. The antitumor efficacy of these two conjugates outperformed parent PTX formulation and Abraxane in nude mice bearing breast cancer cells MCF-7. More importantly, the conjugate S treatment eliminated all the xenograft tumors without causing any mice body weight loss in mice model. This study revealed that the dextran-based dual drug conjugates may represent an effective and innovative way to deliver anticancer agents to a variety of tumors.
在这项研究中，开发并评估了一种新型的基于羧甲基葡聚糖（CMD）的双药物递送系统，用于将两种水不溶性药物递送到肿瘤部位以发挥抗癌活性。紫杉醇（PTX）和二十二碳六烯酸（DHA）与 CMD 共价连接，分别生成含有氨基酸甘氨酸-甘氨酸或赖氨酸-甘氨酸-甘氨酸的不同连接子的 CMD-DHA-PTX 缀合物 S 和缀合物 L。两种缀合物均具有高的 PTX 载药量和增强的水溶性，并且能够自组装成纳米粒子，纳米粒子的尺寸范围为 88.7nm 至 94.7nm。这两种缀合物在血浆和癌细胞中持续释放游离的 PTX。与母体 PTX、Abraxane 和缀合物 L 相比，缀合物 S 表现出改善的药代动力学参数和更高的肿瘤部位分布程度。在荷乳腺癌细胞 MCF-7 的裸鼠中，这两种缀合物的抗肿瘤疗效优于母体 PTX 制剂和 Abraxane。更重要的是，在小鼠模型中，缀合物 S 治疗消除了所有异种移植物肿瘤，而没有导致任何小鼠体重减轻。这项研究表明，基于葡聚糖的双药物缀合物可能代表了一种将抗癌剂递送到各种肿瘤的有效和创新的方法。
