Document Detail


Design and Biological Evaluation of Cell-Penetrating Peptide-Doxorubicin Conjugates as Prodrugs.
MedLine Citation:
PMID:  23301519     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
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 covalently (cyclic [W(RW)4]-Dox and linear (RW)4-Dox) and the corresponding noncovalent physical mixtures of the peptides and Dox was 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 folds 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:
Amir Nasrolahi Shirazi; Rakesh K Tiwari; Bhupender S Chhikara; Dindyal Mandal; Keykavous Parang
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2013-1-9
Journal Detail:
Title:  Molecular pharmaceutics     Volume:  -     ISSN:  1543-8392     ISO Abbreviation:  Mol. Pharm.     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2013-1-10     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101197791     Medline TA:  Mol Pharm     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
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