Stability in plasmas of various species of HPMA Copolymer-PGE1 conjugates
Stability in plasmas of various species of HPMA Copolymer-PGE1 conjugates
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DOI：
10.1007/s11095-007-9449-3
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发表时间：
2007-12-01
影响因子：
3.7
通讯作者：
Kopecek, Jindrich
中科院分区：
文献类型：
--
作者：
Pan, Huaizhong;Kopeckova, Pavla;Kopecek, Jindrich
目的。目的：测定不同种类的人血浆中HPMA共聚物-前列腺素E-1 （PGE(1)）偶联物的稳定性，并鉴定导致酯键断裂的酶。结合物在37℃的人、大鼠和小鼠血浆中孵育，存在或不存在特异性酯酶抑制剂。用高效液相色谱法分析释放的PGE(1)。为了评价共轭物的构象对PGE(1)释放速率的影响，通过疏水侧链的附着对其结构进行了修饰。PGE(1)的释放速率具有很强的物种依赖性。虽然偶联物在人血浆中稳定，但PGE(1)在大鼠或小鼠血浆中的释放量很大。在大鼠血浆中，酯键裂解主要由丁基胆碱酯酶催化；在小鼠血浆中，除丁基胆碱酯酶外，羧酸酯酶也参与了卵裂。紧凑聚合物线圈的形成稳定了酯键。HPMA共聚物- pge(1)偶联物是治疗骨质疏松症的新疗法。观察到的酯键血浆稳定性的物种差异是重要的，因为去卵巢大鼠模型被FDA推荐用于临床前评估。
Purpose. To determine the stability of HPMA copolymer-prostaglandin E-1 (PGE(1)) conjugates in plasmas of different species and to identify the enzymes responsible for the cleavage of the ester bond.Methods. The conjugates were incubated in human, rat, and mouse plasma at 37 degrees C in the presence and absence of specific esterase inhibitors. The released PGE(1) was analyzed using an HPLC assay. To evaluate the effect of the conformation of the conjugate on the rate of PGE(1) release, its structure was modified by the attachment of hydrophobic side chains.Results. The rate of PGE(1) release was strongly species dependent. Whereas the conjugate was stable in human plasma, the PGE(1) release in rat or mouse plasma was substantial. In rat plasma, the ester bond cleavage was mainly catalyzed by butyrylcholinesterase; in mouse plasma, in addition to butyrylcholinesterase, carboxylesterase also contributed to the cleavage. The formation of compact polymer coils stabilized the ester bond.Conclusions. HPMA copolymer-PGE(1) conjugates are strong candidates as novel therapeutics for the treatment of osteoporosis. The observed species differences in plasma stability of ester bonds are of importance, because the ovariectomized rat model is recommended by the FDA for pre-clinical evaluation.