Long circulation and cytotoxicity of PEGylated gemcitabine and its potential for the treatment of pancreatic cancer
Long circulation and cytotoxicity of PEGylated gemcitabine and its potential for the treatment of pancreatic cancer
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DOI：
10.1016/j.biomaterials.2010.08.010
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发表时间：
2010-12-01
期刊：
影响因子：
14
通讯作者：
Sahoo, Sanjeeb K.
中科院分区：
文献类型：
--
作者：
Vandana, Mallaredy;Sahoo, Sanjeeb K.
吉西他滨[2 '，2'-二氟-2 '-脱氧胞苷（dFdC）]是一种低分子量脱氧胞苷类似物，抑制细胞DNA合成。目前，它是美国食品和药物管理局（FDA）批准用于治疗胰腺癌的一线药物。然而，使用吉西他滨作为抗癌剂的努力受到其短循环时间和快速代谢的限制，这反映在低肿瘤摄取和细胞内作用。在这方面，聚合物药物缀合物已经产生了通过化学修饰来改善吉西他滨的细胞毒性效率和生物利用度的方法。本研究描述了聚乙二醇化吉西他滨的水溶性制剂的合成，其特征在于通过FT IR，H-1 NMR和RP-HPLC色谱。如在动物模型中研究的，PEG化吉西他滨在血浆中具有延长的循环时间。这最终导致胰腺癌细胞系（MIA PaCa 2和PANC 1）中细胞毒性和凋亡诱导活性的显著改善。因此，这些发现证明聚乙二醇化吉西他滨是通过静脉内施用进行治疗的理想方法。这种方法的成功临床应用可以显著有助于胰腺癌的治疗。(C)2010爱思唯尔有限公司版权所有。
Gemcitabine [2', 2'-difluoro-2'-deoxycytidine (dFdC)] is a low molecular weight, deoxycytidine analog inhibiting cellular DNA synthesis. Currently, it is the frontline drug approved by Food and Drug Administration (FDA) for the treatment of pancreatic cancer. However, efforts to use gemcitabine as an anti-cancer agent have been limited by its short circulation time and rapid metabolism that reflects in low tumor uptake and intracellular action. Polymer drug conjugates, in this regard have spawned an approach to improve the cytotoxicity efficiency and bioavailability of gemcitabine by chemical modification. The present study describes the synthesis of a water soluble formulation of PEGylated gemcitabine characterized by FT IR, H-1 NMR and RP-HPLC chromatography. The PEGylated gemcitabine has a prolonged circulation time in plasma as studied in an animal model. This eventually caused a marked improvement in the cytotoxicity and apoptosis-inducing activity in pancreatic cancer cell lines (MIA PaCa 2 and PANC 1). Hence, these findings demonstrate the PEGylated gemcitabine is a desirable approach for therapy by intravenous administration. Successful clinical application of this approach can significantly contribute to the treatment of pancreatic cancer. (C) 2010 Elsevier Ltd. All rights reserved.