Shi XiaoLi, Lin Xiao, Zheng XiangWei, Feng Yi, Shen Lan
College of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, People's Republic of China.
Engineering Research Center of Modern Preparation Technology of TCM of Ministry of Education, Shanghai University of Traditional Chinese Medicine, Shanghai, People's Republic of China.
Int J Nanomedicine. 2014 Nov 28;9:5555-63. doi: 10.2147/IJN.S71819. eCollection 2014.
Radix Ophiopogonis polysaccharide (ROP), a highly hydrophilic macromolecule, has a unique anti-ischemic action in the myocardium. One of the main problems with its use is its relatively short half-life in vivo. To solve this problem, injectable long-acting drug delivery systems, which combine mono-PEGylation (PEG, polyethylene glycol) with the in situ formation of poly(D,L-lactide-co-glycolide) copolymer (PLGA) depots, were tested in this study.
Through a moderate coupling reaction between 20 kDa amino-terminated methoxy-PEG and excessive ROP with activated hydroxyls, a long-circulating and bioactive mono-PEGylated ROP was prepared and characterized. A reasonable and applicable range of PLGA formulations loaded with the mono-PEGylated ROP were prepared, characterized, and evaluated in vivo.
Relative to ROP, the half-life of which was only 0.5 hours, the conjugate alone, following subcutaneous administration, showed markedly prolonged retention in the systemic circulation, with a mean residence time in vivo of approximately 2.76 days. In combination with in situ-forming PLGA depots, the residence time of the conjugate in vivo was prolonged further. In particular, a long-lasting and steady plasma exposure for nearly a month was achieved by the formulation comprising 40% 30 kDa PLGA in N-methyl-2-pyrrolidone.
Long-lasting and steady drug exposure could be achieved using mono-PEGylation in combination with in situ formation of PLGA depots. Such a combination with ROP would be promising for long-term prophylaxis and/or treatment of myocardial ischemia. For high-dose and highly hydrophilic macromolecular drugs like ROP, more than one preparation technology might be needed to achieve week-long or month-long delivery per dosing.
麦冬多糖（ROP）是一种高度亲水的大分子，在心肌中具有独特的抗缺血作用。其使用的主要问题之一是在体内半衰期相对较短。为解决这一问题，本研究测试了将单甲氧基聚乙二醇化（PEG，聚乙二醇）与聚（D，L-丙交酯-共-乙交酯）共聚物（PLGA）原位形成储库相结合的可注射长效药物递送系统。
通过20 kDa氨基末端甲氧基聚乙二醇与过量带有活化羟基的ROP之间的适度偶联反应，制备并表征了具有长循环和生物活性的单甲氧基聚乙二醇化ROP。制备了负载单甲氧基聚乙二醇化ROP的合理且适用范围的PLGA制剂，进行了表征并在体内进行了评估。
相对于半衰期仅为0.5小时的ROP，单独的偶联物皮下给药后在体循环中的保留时间明显延长，体内平均驻留时间约为2.76天。与原位形成的PLGA储库相结合，偶联物在体内的驻留时间进一步延长。特别是，通过在N-甲基-2-吡咯烷酮中包含40% 30 kDa PLGA的制剂实现了近一个月的持久且稳定的血浆暴露。
使用单甲氧基聚乙二醇化与PLGA储库原位形成相结合可实现持久且稳定的药物暴露。这种与ROP的组合对于心肌缺血的长期预防和/或治疗具有前景。对于像ROP这样的高剂量和高亲水性大分子药物，可能需要不止一种制备技术来实现每次给药长达一周或一个月的递送。
