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Cellular uptake and cytotoxicity of drug-peptide conjugates regulated by conjugation site.

ABSTRACT: Conjugation of anticancer drugs to hydrophilic peptides such as Tat is a widely adopted strategy to improve the drug's 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.

SUBMITTER: Zhang P

PROVIDER: S-EPMC3651882 | biostudies-literature | 2013 Apr

REPOSITORIES: biostudies-literature

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Cellular uptake and cytotoxicity of drug-peptide conjugates regulated by conjugation site.

Zhang Pengcheng P Cheetham Andrew G AG Lock Lye Lin LL Cui Honggang H

Bioconjugate chemistry 20130326 4

Conjugation of anticancer drugs to hydrophilic peptides such as Tat is a widely adopted strategy to improve the drug's 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 conju ...[more]

PMID: 23514455

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