Abu-Fayyad Ahmed, Nazzal Sami
College of Health and Pharmaceutical Sciences, School of Pharmacy, University of Louisiana at Monroe, Monroe, LA, USA.
College of Health and Pharmaceutical Sciences, School of Pharmacy, University of Louisiana at Monroe, Monroe, LA, USA; College of Pharmacy, Taipei Medical University, Taipei, Taiwan.
Int J Pharm. 2017 Aug 7;528(1-2):463-470. doi: 10.1016/j.ijpharm.2017.06.031. Epub 2017 Jun 13.
Gemcitabine is the first line therapy for pancreatic cancer. It is, however, extensively metabolized to the inactive form by deamination enzymatic reaction. Conjugation of gemcitabine with fatty acids on its 4-amino group was found to protect it from deamination deactivation reaction. The objective of the present study was to test the in-vitro anticancer activity of gemcitabine conjugated to the γ-tocotrienol isomer of vitamin E against pancreatic tumor cells. This objective was based on reported studies in which it was demonstrated that free tocotrienol isomers of vitamin E can potentiate the anticancer activity of gemcitabine. To accomplish this objective, a full synthesis scheme for gemcitabine conjugation to fatty acids (stearic and linoleic) and the tocopherol and tocotrienol isomers of vitamin E (α-T and γ-T3) was presented. The conjugates were characterized by H NMR and mass spectrometry analysis and tested for their susceptibility to deamination. Also discussed is the impact of entrapping the conjugates into nanoemulsions on the physiochemical properties of the delivery system and the in vitro anticancer activity of gemcitabine against Bx-PC-3 and PNAC-1 pancreatic cancer cells. In-vitro enzymatic deamination study showed that the γ-T3 conjugate of gemcitabine was least affected by deamination deactivation reaction when compared with the free and conjugated gemcitabine in solution. Furthermore, in-vitro cytotoxicity study demonstrated that entrapment of gemcitabine-lipid conjugates into nanoemulsions significantly enhanced their anticancer activity when compared to the free drug. It was concluded that conjugation to the γ-T3 isomer is a viable option for gemcitabine delivery and is worthy of further investigation.
吉西他滨是胰腺癌的一线治疗药物。然而，它会通过脱氨酶促反应广泛代谢为无活性形式。研究发现，吉西他滨在其4-氨基上与脂肪酸结合可保护其免受脱氨失活反应的影响。本研究的目的是测试与维生素E的γ-生育三烯酚异构体结合的吉西他滨对胰腺肿瘤细胞的体外抗癌活性。该目的基于已报道的研究，其中表明维生素E的游离生育三烯酚异构体可增强吉西他滨的抗癌活性。为实现这一目标，提出了吉西他滨与脂肪酸（硬脂酸和亚油酸）以及维生素E的生育酚和生育三烯酚异构体（α-T和γ-T3）结合的完整合成方案。通过核磁共振氢谱和质谱分析对结合物进行了表征，并测试了它们的脱氨敏感性。还讨论了将结合物包裹在纳米乳液中对递送系统物理化学性质以及吉西他滨对Bx-PC-3和PNAC-1胰腺癌细胞的体外抗癌活性的影响。体外酶促脱氨研究表明，与溶液中的游离吉西他滨和结合型吉西他滨相比，吉西他滨的γ-T3结合物受脱氨失活反应的影响最小。此外，体外细胞毒性研究表明，与游离药物相比，将吉西他滨-脂质结合物包裹在纳米乳液中可显著增强其抗癌活性。得出的结论是，与γ-T3异构体结合是吉西他滨递送的一个可行选择，值得进一步研究。
