Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Shandong University, Jinan, Shandong, PR China.
Int J Biol Macromol. 2012 May 1;50(4):974-80. doi: 10.1016/j.ijbiomac.2012.02.019. Epub 2012 Feb 25.
A series of methoxy poly(ethylene glycol)-succinyl-5'-O-zidovudine conjugates (mPEG-succinyl-AZT) with different molecular weight (M(w): 750 Da, 2, 5 or 10 kDa) of mPEG were synthesized and characterized by Fourier transform infrared (FTIR) spectroscopy, (1)H nuclear magnetic resonance ((1)H NMR) spectroscopy, and matrix-assisted laser desorption/ionization time of flight mass (MALDI TOF MS) spectrometry analysis. All conjugates showed good stability in vitro release experiments, and good anti-HIV activity and low cytotoxicity in MT-4 cells, in which, mPEG(750)-succinyl-AZT exhibited good inhibition to wild-type viruses (strains IIIB and ROD) with EC(50) values of 0.11 and 0.090 μmol/L, respectively, and it showed no cytotoxicity up to 110 μmol/L. Oral pharmacokinetic study in rats showed the half-life time (T(1/2)) of all conjugates are prolonged compared to free AZT. Especially, mPEG(750)-succinyl-AZT displayed a ~2.3-fold prolonged half-life and approximately 224% increased bioavailability of AZT.
一系列不同相对分子质量（mPEG：750 Da、2、5 或 10 kDa）甲氧基聚乙二醇琥珀酰-5′-叠氮胸苷（mPEG-琥珀酰-AZT）偶联物被合成并通过傅里叶变换红外（FTIR）光谱、（1）H 核磁共振（1H NMR）光谱和基质辅助激光解吸/电离飞行时间质谱（MALDI-TOF MS）分析进行了表征。所有偶联物在体外释放实验中均表现出良好的稳定性，在 MT-4 细胞中具有良好的抗 HIV 活性和低细胞毒性，其中 mPEG（750）-琥珀酰-AZT 对野生型病毒（株 IIIB 和 ROD）具有良好的抑制作用，EC50 值分别为 0.11 和 0.090 μmol/L，最高 110 μmol/L 时无细胞毒性。大鼠口服药代动力学研究表明，与游离 AZT 相比，所有偶联物的半衰期（T（1/2））均延长。特别是 mPEG（750）-琥珀酰-AZT 显示出约 2.3 倍延长的半衰期和约 224%增加的 AZT 生物利用度。
