Cellular Uptake and Cytotoxicity of Drug鈥揚eptide Conjugates Regulated by Conjugation Site

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• 作者：Pengcheng Zhang ; Andrew G. Cheetham ; Lye Lin Lock ; Honggang Cui
• 刊名：Bioconjugate Chemistry
• 出版年：2013
• 出版时间：April 17, 2013
• 年：2013
• 卷：24
• 期：4
• 页码：604-613
• 全文大小：475K
• 年卷期：v.24,no.4(April 17, 2013)
• ISSN：1520-4812

文摘

Conjugation of anticancer drugs to hydrophilic peptides such as Tat is a widely adopted strategy to improve the drug鈥檚 solubility, cellular uptake, and potency against cancerous cells. Here we report that attachment of an anticancer drug doxorubicin to the N- or C-terminal of the Tat peptide can have a significant impact on their cellular uptake and cytotoxicity against both drug-sensitive and drug-resistant cancer cells. We observed higher cellular uptake by both cell lines for C-terminal conjugate relative to the N-terminal analogue. Our results reveal that the C-terminal conjugate partially overcame the multidrug resistance of cervical cancer cells, while the N-terminal conjugate showed no significant improvement in cytotoxicity when compared with free doxorubicin. We also found that both N- and C-conjugates offer a mechanism to circumvent drug efflux associated with multidrug resistance.