Department of Experimental Oncology, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, 53-114, Wroclaw, Poland.
Invest New Drugs. 2021 Feb;39(1):15-23. doi: 10.1007/s10637-020-00972-9. Epub 2020 Jul 8.
Clinical and experimental cancer therapy is multifaceted; one such facet is the use of drug carriers. Drug carriers are various nano- and macromolecules, e.g., oligosaccharides, proteins, and liposomes. The present study aimed to verify the suitability of cellulose as a carrier for methotrexate (MTX). Hydroxyethylcellulose, with a molecular weight of 90 kDa and soluble in water, was used. Methotrexate was linked to cellulose by methyl ester bonds. A conjugate containing on average 9.5 molecules of MTX per molecule of cellulose was developed. Gel filtration HPLC analysis showed that the conjugate contained approximately 2% free drug. Dynamic light scattering analysis showed an increase in the polydispersity of the conjugate. The degradation of the conjugate in phosphate buffer and plasma followed first-order kinetics. The conjugate showed the lowest stability (half-life 154 h) in plasma. The conjugate showed 10-fold lower cytotoxicity to the 4 T1 mammary tumour cell line than the free drug. In the in vivo experiment to treat orthotopically implanted mammary tumours, the conjugate and the free drug, both applied intravenously, showed maximum inhibition of tumour growth of 48.4% and 11.2%, respectively. In conclusion, cellulose, which is a non-biodegradable chain glucose polymer, can be successfully used as a drug carrier, which opens up new research perspectives.
临床与实验癌症治疗是多方面的；其中一个方面是使用药物载体。药物载体是各种纳米和大分子，例如寡糖、蛋白质和脂质体。本研究旨在验证纤维素作为甲氨蝶呤（MTX）载体的适用性。使用羟乙基纤维素，分子量为 90 kDa，可溶于水。甲氨蝶呤通过甲酯键与纤维素结合。开发了一种平均每个纤维素分子含有 9.5 个 MTX 分子的缀合物。凝胶过滤 HPLC 分析表明，缀合物中含有约 2%的游离药物。动态光散射分析表明，缀合物的多分散性增加。在磷酸盐缓冲液和血浆中，缀合物的降解遵循一级动力学。在血浆中，缀合物的稳定性最低（半衰期 154 h）。与游离药物相比，缀合物对 4T1 乳腺肿瘤细胞系的细胞毒性低 10 倍。在治疗原位植入乳腺肿瘤的体内实验中，静脉注射应用缀合物和游离药物，分别最大抑制肿瘤生长 48.4%和 11.2%。总之，纤维素是一种不可生物降解的链葡萄糖聚合物，可成功用作药物载体，为研究开辟了新的视角。
