title: 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.
authors.affiliation: Department of Chemical and Biomolecular Engineering and Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD 21218, USA.
authors.forename: Pengcheng
authors.initials: P
authors.lastname: Zhang
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Cheetham
authors.forename: Lye Lin
authors.initials: LL
authors.lastname: Lock
authors.forename: Honggang
authors.initials: H
authors.lastname: Cui
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D018432:Drug Resistance, Multiple / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D007624:KB Cells; D015394:Molecular Structure; D009842:Oligopeptides / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*
chemical_list: D000970:Antineoplastic Agents; D009842:Oligopeptides