Design and biological evaluation of cell-penetrating peptide-doxorubicin conjugates as prodrugs

Amir Nasrolahi Shirazi, Rakesh Tiwari, Bhupender S. Chhikara, Dindyal Mandal, Keykavous Parang

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)488-499
Number of pages12
JournalMolecular Pharmaceutics
Volume10
Issue number2
DOIs
StatePublished - Feb 4 2013
Externally publishedYes

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Keywords

  • anticancer
  • cell-penetrating peptides
  • cellular uptake
  • cyclic peptides
  • doxorubicin

ASJC Scopus subject areas

  • Pharmaceutical Science
  • Molecular Medicine
  • Drug Discovery

Cite this

Nasrolahi Shirazi, A., Tiwari, R., Chhikara, B. S., Mandal, D., & Parang, K. (2013). Design and biological evaluation of cell-penetrating peptide-doxorubicin conjugates as prodrugs. Molecular Pharmaceutics, 10(2), 488-499. https://doi.org/10.1021/mp3004034