title: Design and biological evaluation of cell-penetrating peptide-doxorubicin conjugates as prodrugs.
abstract: Doxorubicin (Dox) is a hydrophilic anticancer drug that has short retention time due to the efficient efflux in some cancer cells (e.g., ovarian adenocarcinoma SK-OV-3). Cyclic [W(RW)(4)] and the corresponding linear peptide (RW)(4) were conjugated with Dox through an appropriate linker to afford cyclic [W(RW)(4)]-Dox and linear (RW)(4)-Dox conjugates to enhance the cellular uptake and cellular retention of the parent drug for sustained anticancer activity. Comparative antiproliferative assays between covalent (cyclic [W(RW)(4)]-Dox and linear (RW)(4)-Dox) and the corresponding noncovalent physical mixtures of the peptides and Dox were performed. Cyclic [W(RW)(4)]-Dox inhibited the cell proliferation of human leukemia (CCRF-CEM) (62-73%), ovarian adenocarcinoma (SK-OV-3) (51-74%), colorectal carcinoma (HCT-116) (50-67%), and breast carcinoma (MDA-MB-468) (60-79%) cells at a concentration of 1 μM after 72-120 h of incubation. Cyclic [W(RW)(4)]-Dox exhibited higher antiproliferative activity than linear (RW)(4)-Dox in all cancer cells with the highest activity observed after 72 h. Flow cytometry analysis showed 3.6-fold higher cellular uptake of cyclic [W(RW)(4)]-Dox than Dox alone in SK-OV-3 cells after 24 h incubation. The cellular hydrolysis study showed that 99% of cyclic [W(RW)(4)]-Dox was hydrolyzed intracellularly within 72 h and released Dox. These data suggest that cyclic [W(RW)(4)]-Dox can be used as a potential prodrug for improving the cellular delivery and retention of Dox.
authors.affiliation: Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, 7 Greenhouse Road, Kingston, Rhode Island 02881, United States.
authors.forename: Amir
authors.initials: A
authors.lastname: Nasrolahi Shirazi
authors.forename: Rakesh
authors.initials: R
authors.lastname: Tiwari
authors.forename: Bhupender S
authors.initials: BS
authors.lastname: Chhikara
authors.forename: Dindyal
authors.initials: D
authors.lastname: Mandal
authors.forename: Keykavous
authors.initials: K
authors.lastname: Parang
mesh_terms: D057846:Cell-Penetrating Peptides / Q000737:chemistry* / Q000378:metabolism*; D004317:Doxorubicin / Q000737:chemistry* / Q000378:metabolism*; D015195:Drug Design; D019804:Mesalamine / Q000737:chemistry / Q000378:metabolism; D015394:Molecular Structure; D011355:Prodrugs / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D057846:Cell-Penetrating Peptides; D011355:Prodrugs; D019804:Mesalamine; D004317:Doxorubicin