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PEGylated leuprolide with improved pharmacokinetic properties.
Bioorganic & Medicinal Chemistry ( IF 3.3 ) Pub Date : 2020-01-07 , DOI: 10.1016/j.bmc.2020.115306 Mian Fu 1 , Xiaomei Zhuang 2 , Tianhong Zhang 2 , Ying Guan 1 , Qingbin Meng 2 , Yongjun Zhang 1
Bioorganic & Medicinal Chemistry ( IF 3.3 ) Pub Date : 2020-01-07 , DOI: 10.1016/j.bmc.2020.115306 Mian Fu 1 , Xiaomei Zhuang 2 , Tianhong Zhang 2 , Ying Guan 1 , Qingbin Meng 2 , Yongjun Zhang 1
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Leuprolide, a gonadotropin-releasing hormone (GnRH) agonist widely used in androgen deprivation therapy for the treatment of advanced prostate cancer, suffers from a short circulating half-life like other peptide therapeutics. As an attempt to improve its pharmacokinetic properties, two PEGylated leuprolides with different molecular weight were synthesized utilizing N-hydroxysuccinimidyl (NHS) conjugation chemistry. The reaction conditions, including reaction temperature, reaction time and feed ratio of the reactants, were optimized to obtain a higher yield. Reverse-phase high performance liquid chromatography (RP-HPLC) characterization indicates a high purity of the resulting conjugates. Matrix-assisted laser desorption mass spectrometry (MALDI-MS) characterization suggests a 1:1 PEGylation. 1H NMR study reveals that the reaction occurs on the imidazolyl group on the histidine residue and the conjugates are stable in pH7.4 aqueous solutions. The in vitro bioactivity of the conjugates was evaluated using both hormone-sensitive and hormone-insensitive cell lines. It was found that the PEGylated peptides can still counteract the stimulatory action of androgens and the mitogenic action of epidermal growth factor on cell proliferation. The in vivo bioactivity of the conjugates was also tested. Like the unmodified peptide, administration of the conjugates to male rats leads to an initial testosterone surge, followed by a suppression of testosterone secretion. Pharmacokinetics of the drugs after i.v. and s.c. administrations were determined. In both cases, a prolonged circulating half-life, an increased AUC, and a decreased Cl_F were observed for the PEGylated drugs.
中文翻译：
具有改善的药代动力学特性的聚乙二醇化亮丙瑞林。
Leuprolide是一种广泛用于雄激素剥夺治疗晚期前列腺癌的促性腺激素释放激素（GnRH）激动剂，与其他肽类疗法一样，其循环半衰期短。为了改善其药代动力学性质，利用N-羟基琥珀酰亚胺基（NHS）结合化学方法合成了两种分子量不同的聚乙二醇化亮丙瑞林。优化反应条件，包括反应温度，反应时间和反应物的进料比，以获得更高的收率。反相高效液相色谱（RP-HPLC）表征表明所得缀合物的纯度高。基质辅助激光解吸质谱（MALDI-MS）表征表明1：1 PEG化。1 H NMR研究表明该反应发生在组氨酸残基的咪唑基上，并且缀合物在pH7.4水溶液中稳定。使用激素敏感和激素不敏感的细胞系评估缀合物的体外生物活性。发现聚乙二醇化的肽仍然可以抵消雄激素的刺激作用和表皮生长因子对细胞增殖的促有丝分裂作用。还测试了缀合物的体内生物活性。像未修饰的肽一样，对雄性大鼠施用缀合物会导致最初的睾丸激素激增，然后抑制睾丸激素的分泌。确定了静脉内和皮下给药后药物的药代动力学。在这两种情况下，循环半衰期延长，AUC增加，
更新日期：2020-01-07
中文翻译：
具有改善的药代动力学特性的聚乙二醇化亮丙瑞林。
Leuprolide是一种广泛用于雄激素剥夺治疗晚期前列腺癌的促性腺激素释放激素（GnRH）激动剂，与其他肽类疗法一样，其循环半衰期短。为了改善其药代动力学性质，利用N-羟基琥珀酰亚胺基（NHS）结合化学方法合成了两种分子量不同的聚乙二醇化亮丙瑞林。优化反应条件，包括反应温度，反应时间和反应物的进料比，以获得更高的收率。反相高效液相色谱（RP-HPLC）表征表明所得缀合物的纯度高。基质辅助激光解吸质谱（MALDI-MS）表征表明1：1 PEG化。1 H NMR研究表明该反应发生在组氨酸残基的咪唑基上，并且缀合物在pH7.4水溶液中稳定。使用激素敏感和激素不敏感的细胞系评估缀合物的体外生物活性。发现聚乙二醇化的肽仍然可以抵消雄激素的刺激作用和表皮生长因子对细胞增殖的促有丝分裂作用。还测试了缀合物的体内生物活性。像未修饰的肽一样，对雄性大鼠施用缀合物会导致最初的睾丸激素激增，然后抑制睾丸激素的分泌。确定了静脉内和皮下给药后药物的药代动力学。在这两种情况下，循环半衰期延长，AUC增加，
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