Ravichandran Vasanthan, Kothandaraman Gayathri P, Bories Christian, Loiseau Philippe M, Jayakrishnan A
Biomaterials Laboratory, Department of Biotechnology, Bhupat and Jyothi Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai 600036, Tamil Nadu, India.
Chimiothérapie Antiparasitaire, UMR 8076 CNRS BioCIS, Faculté de Pharmacie, Université Paris-Sud, 5, Rue Jean-Baptiste Clement, F-92296, Chatenay-Malabry, France.
J Nanosci Nanotechnol. 2018 Apr 1;18(4):2405-2414. doi: 10.1166/jnn.2018.14296.
While many naturally occurring polysaccharides have been widely used as drug carriers, there are two main drawbacks in their use: the first is their physical properties such as molecular weight, branching, type of glycosidic linkages and solubility depend on their source and the method of isolation and purification, the second is many of them are contaminated with proteins and protein removal is essential for preventing immune reactions. Synthetic polysaccharides on the other hand can be tailor made from their respective monomers with consistent physical properties and are, free from protein contamination, both being significant advantages in their use. Although, the synthesis of polysaccharides such as polyglucose, polymannose, polygalactose etc., by the polycondensation of their respective monomers have been reported more than half a century ago, their use as drug carriers have not received any attention so far. In this report, we show that polyglucose (PG) having a weight average molar mass of 37,000 g/mol can be synthesized in a single step by the melt polycondensation of glucose in over 70% yield. Oxidation using sodium periodate generated aldehyde functions on the polymer. Amphotericin B, (AmB) a water-insoluble polyene antibiotic was chosen as a model drug to couple onto periodate oxidized PG via imine linkage at ~20 wt% concentration. The drug loading capacity of the conjugates was above 90%. Further reduction using sodium borohydride gave the more stable amine conjugates with any residual aldehyde on the polymer backbone getting reduced to hydroxyl groups. The conjugates were highly soluble in water and stable on storage. At ten times the concentration of AmB, the conjugates produced negligible hemolysis to human blood. The AmB conjugates were then evaluated for their anti-fungal activity against C. albicans and A. fumigatus and anti-leishmanial activity against different strains of L. donovani in culture. The conjugates showed potent anti-fungal and anti-leishmanial activity. The use of synthetic polysaccharides in drug delivery and in other biomedical applications will have many potential advantages.
虽然许多天然存在的多糖已被广泛用作药物载体，但在其使用中存在两个主要缺点：第一个是它们的物理性质，如分子量、分支、糖苷键类型和溶解度取决于其来源以及分离和纯化方法；第二个是它们中的许多都被蛋白质污染，去除蛋白质对于防止免疫反应至关重要。另一方面，合成多糖可以由各自的单体定制而成，具有一致的物理性质，并且没有蛋白质污染，这两者在其使用中都是显著的优势。尽管半个多世纪前就已报道了通过各自单体的缩聚反应合成多糖，如聚葡萄糖、聚甘露糖、聚半乳糖等，但它们作为药物载体的应用至今尚未受到任何关注。在本报告中，我们表明通过葡萄糖的熔融缩聚可以一步合成重均摩尔质量为37,000 g/mol的聚葡萄糖（PG），产率超过70%。使用高碘酸钠氧化在聚合物上产生醛基功能。选择两性霉素B（AmB），一种水不溶性多烯抗生素，作为模型药物，以约20 wt%的浓度通过亚胺键连接到高碘酸钠氧化的PG上。缀合物的载药能力高于90%。使用硼氢化钠进一步还原得到更稳定的胺缀合物，聚合物主链上的任何残留醛基都被还原为羟基。缀合物在水中高度可溶且储存稳定。在AmB浓度的十倍下，缀合物对人血产生的溶血作用可忽略不计。然后评估了AmB缀合物对白色念珠菌和烟曲霉的抗真菌活性以及对杜氏利什曼原虫不同菌株在培养中的抗利什曼活性。缀合物显示出强大的抗真菌和抗利什曼活性。合成多糖在药物递送和其他生物医学应用中的使用将具有许多潜在优势。
