当前位置: X-MOL 学术Glycobiology › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Synthesis and characterization of heparosan-granulocyte-colony stimulating factor conjugates: a natural sugar-based drug delivery system to treat neutropenia
Glycobiology ( IF 4.3 ) Pub Date : 2017-09-08 , DOI: 10.1093/glycob/cwx072
Wei Jing 1 , Jonathan W Roberts 1 , Dixy E Green 2 , Andrew Almond 3 , Paul L DeAngelis 2
Affiliation  

Many injectable drugs require delivery strategies for enhancing their pharmacokinetics due to rapid loss via renal filtration if possess low molecular weight (<60–70 kDa) and/or clearance by the body's components (e.g., proteases, antibodies, high-efficiency receptors) in their native form. FDA-approved polyethylene glycol (PEG) is a vehicle for improving therapeutics, but artificial polymers have potential biocompatibility and immunogenicity liabilities. Here, we utilized a natural vertebrate carbohydrate, heparosan (HEP), the biosynthetic precursor of heparan sulfate and heparin, to enhance performance of a biologic drug. The HEP polysaccharide was stable with a long half-life (~8 days for 99-kDa chain) in the nonhuman primate bloodstream, but was efficiently degraded to very short oligosaccharides when internalized by cells, and then excreted into urine and feces. Several HEP-modified human granulocyte-colony stimulating factor (G-CSF) conjugates were synthesized with defined quasi-monodisperse HEP polysaccharide chains. Single dosing of 55- or 99-kDa HEP-G-CSF in rats increased blood neutrophil levels comparable to PEG-G-CSF conjugates. Repeated dosing of HEP-G-CSF or HEP alone for 2 weeks did not cause HEP-specific toxic effects in rats. HEP did not possess the anticoagulant behavior of its daughter, heparin, based on testing in rats or clinical diagnostic assays with human plasma. Neither anti-HEP IgG nor IgM antibodies were detected in a long-term (9 doses over 7 months) immunogenicity study of the HEP-drug conjugate with rats. These proof-of-concept experiments with HEP-G-CSF indicate that it is a valid drug candidate for neutropenia and suggest the potential of this HEP-based platform as a safe alternative delivery vehicle for other therapeutics.

中文翻译:

肝素-粒细胞-集落刺激因子偶联物的合成与表征:天然糖基药物递送系统,用于治疗中性粒细胞减少症

如果具有低分子量(<60–70 kDa)和/或被人体的成分(例如,蛋白酶,抗体,高效受体)清除,许多注射药物需要通过肾过滤快速流失的策略来增强其药代动力学。他们的本机形式。FDA批准的聚乙二醇(PEG)是改善治疗方法的载体,但人工聚合物具有潜在的生物相容性和免疫原性。在这里,我们利用天然脊椎动物碳水化合物,肝素聚糖(HEP)(硫酸乙酰肝素和肝素的生物合成前体)来增强生物药物的性能。HEP多糖在非人灵长类动物血流中具有较长的半衰期(〜8天,对于99 kDa链)稳定,但被细胞内化后可有效降解为非常短的寡糖,然后排泄到尿液和粪便中。合成了几种具有确定的准单分散HEP多糖链的HEP修饰的人类粒细胞集落刺激因子(G-CSF)共轭物。与PEG-G-CSF缀合物相比,在大鼠中单次给药55-kDa或99-kDa的HEP-G-CSF可增加血液中性粒细胞水平。重复给药HEP-G-CSF或单独使用HEP 2周不会对大鼠产生HEP特异性毒性作用。根据在大鼠中进行的测试或使用人血浆进行的临床诊断分析,HEP不具有其女儿肝素的抗凝特性。在对HEP药物偶联物进行大鼠的长期(9剂,共7个月)免疫原性研究中,未检测到抗HEP IgG和IgM抗体。
更新日期:2017-10-27
down
wechat
bug