Alexander Peter, Kucera Gregory, Pardee Timothy S
Cancer Biology, Comprehensive Cancer Center of Wake Forest University, Winston-Salem, NC, United States.
Internal Medicine, Wake Forest Baptist Health, Winston-Salem, NC, United States; Cancer Biology, Comprehensive Cancer Center of Wake Forest University, Winston-Salem, NC, United States.
Crit Rev Oncol Hematol. 2016 Apr;100:46-56. doi: 10.1016/j.critrevonc.2016.01.015. Epub 2016 Jan 21.
In the past few decades, nucleoside analog drugs have been used to treat a large variety of cancers. These anti-metabolite drugs mimic nucleosides and interfere with chain lengthening upon incorporation into the DNA or RNA of actively replicating cells. However, efficient delivery of these drugs is limited due to their pharmacokinetic properties, and tumors often develop drug resistance. In addition, nucleoside analogs are generally hydrophilic, resulting in poor bioavailability and impaired blood-brain barrier penetration. Conjugating these drugs to lipids modifies their pharmacokinetic properties and may improve in vivo efficacy. This review will cover recent advances in the field of conjugation of phospholipids to nucleoside analogs. This includes conjugation of myristic acid, 12-thioethyldodecanoic acid, 5-elaidic acid esters, phosphoramidate, and self-emulsifying formulations. Relevant in vitro and in vivo data will be discussed for each drug, as well as any available data from clinical trials.
在过去几十年中,核苷类似物药物已被用于治疗多种癌症。这些抗代谢药物模拟核苷,并在掺入活跃复制细胞的DNA或RNA时干扰链的延长。然而,由于其药代动力学性质,这些药物的有效递送受到限制,并且肿瘤常常产生耐药性。此外,核苷类似物通常具有亲水性,导致生物利用度差且血脑屏障穿透受损。将这些药物与脂质缀合可改变其药代动力学性质,并可能提高体内疗效。本综述将涵盖磷脂与核苷类似物缀合领域的最新进展。这包括肉豆蔻酸、12-硫代乙基十二烷酸、5-反油酸酯、氨基磷酸酯和自乳化制剂的缀合。将讨论每种药物的相关体外和体内数据,以及来自临床试验的任何可用数据。