Engineering Research Center of Modern Preparation Technology of TCM of Ministry of Education, Shanghai University of Traditional Chinese Medicine, Shanghai, PR China.
Eur J Pharm Biopharm. 2011 Nov;79(3):621-6. doi: 10.1016/j.ejpb.2011.07.002. Epub 2011 Jul 19.
PEGylation was found to be a promising approach to improve the anti-myocardial ischemic activity of Radix Ophiopogonis polysaccharide (ROP) by prolonging its retention in plasma. To fully evaluate the effectiveness and safety of this strategy, the tissue distribution of PEGylated ROP was investigated in this study. A long-circulating and bioactive PEGylated ROP with 1.04 mol 20-kDa mPEG per mol ROP ((1.04)P(20k)-R) was prepared by a moderate coupling reaction between the hydroxyl-activated ROP and the amino-terminated mPEG. Its tissue distribution in mice with normal and ischemic myocardium was studied and compared with ROP. The results show that the descending order of tissue distribution of (1.04)P(20k)-R ranked by AUC was kidney, lung, heart, liver, and brain in normal mice and kidney ≈ lung ≈ heart, liver and brain in mice with myocardial ischemia. With the exception of the heart, myocardial ischemia did not cause obvious changes in the distribution of (1.04)P(20k)-R in the other tissues studied. Owing to the enhanced permeability and retention effect caused by ischemia, the AUC of (1.04)P(20k)-R in ischemic hearts was approximately 1.6-fold greater than in normal hearts. Compared with ROP in rats, the distribution tendency of (1.04)P(20k)-R in mouse kidney, brain, and lung was reduced by approximately 42, 1.6, and 1.3 times, respectively, whereas it was increased by approximately 1.3-fold in the liver. The results of this study are highly instructive for the further pharmaceutical development of PEGylated ROP.
聚乙二醇化被发现是一种有前途的方法，可以通过延长其在血浆中的保留时间来提高芦根多糖的抗心肌缺血活性。为了充分评估这种策略的有效性和安全性，本研究考察了聚乙二醇化芦根多糖的组织分布。通过羟基活化的芦根多糖与氨基末端的 20kDa mPEG 的适度偶联反应，制备了一种具有长循环和生物活性的 1.04mol 20kDa mPEG 每摩尔芦根多糖的聚乙二醇化芦根多糖（（1.04）P（20k）-R）。研究了其在正常和缺血心肌小鼠中的组织分布，并与芦根多糖进行了比较。结果表明，（1.04）P（20k）-R 在正常小鼠中的组织分布 AUC 排序降序依次为肾、肺、心、肝和脑，而在心肌缺血小鼠中为肾≈肺≈心、肝和脑。除心脏外，心肌缺血未引起研究的其他组织中（1.04）P（20k）-R 的分布发生明显变化。由于缺血引起的通透性和滞留效应增强，（1.04）P（20k）-R 在缺血心脏中的 AUC 约为正常心脏的 1.6 倍。与大鼠中的芦根多糖相比，（1.04）P（20k）-R 在小鼠肾、脑和肺中的分布趋势分别降低了约 42、1.6 和 1.3 倍，而在肝脏中的分布增加了约 1.3 倍。本研究的结果对聚乙二醇化芦根多糖的进一步药物开发具有重要的指导意义。
