Development of PEGylated doxorubicin-E-[c(RGDfK)2] conjugate for integrin-targeted cancer therapy

Dina Polyak, Claudia Ryppa, Anat Eldar-Boock, Paula Ofek, Ariel Many, Kai Licha, Felix Kratz, Ronit Satchi-Fainaro*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

28 Scopus citations


Doxorubicin (DOX) is extensively used in cancer therapy; however, it is cardiotoxic in cumulative doses and chemoresistance can evolve with prolonged use. Conjugation of a chemotherapeutic agent to a water-soluble polymeric carrier prolongs the circulation life of the drug, promotes its accumulation at the tumor site due to the enhanced permeability and retention (EPR) effect and prevents the drug from extravasating into healthy tissues. We designed and synthesized a delivery system that enables the conjugation of a targeting moiety, Arg-Gly-Asp (RGD) peptidomimetic, on one end of a linear poly(ethylene glycol) (PEG) chain, and DOX on the other end. The drug was bound to the polymer through an acid-sensitive (6-maleimidocaproyl)hydrazone linker. The resulting PEG-DOX-E-[c(RGDfK)2] conjugate actively and selectively targets endothelial and tumor cells overexpressing αvβ3 integrin. Alternatively, we conjugated the PEG-DOX with a control c(RADfK) peptide that does not bind to αvβ3 integrin, resulting in a PEG-DOX-c(RADfK) conjugate. The PEG-DOX-E-[c(RGDfK)2] conjugate and free DOX exhibited similar cytotoxic effect on U87-MG human glioblastoma cells. Interestingly, treatment with the conjugate inhibited the proliferation of DOX-resistant M109 murine lung carcinoma cells at a lower IC50 compared with free DOX and PEG-DOX-c(RADfK). In addition, PEG-DOX-E-[c(RGDfK)2] inhibited the proliferation of human umbilical vein endothelial cells and their attachment to fibrinogen-coated wells. Preliminary in vivo near-infrared studies revealed that a PEG-E-[c(RGDfK)2]-cyanine conjugate preferentially accumulated in mCherry-labeled-DA3 murine mammary tumors inoculated orthotopically in female BALB/c mice. Altogether, our results show a proof of principle for a selective delivery of DOX to endothelial and cancer cells overexpressing αvβ3 integrin.

Original languageEnglish
Pages (from-to)103-113
Number of pages11
JournalPolymers for Advanced Technologies
Issue number1
StatePublished - Jan 2011


  • Doxorubicin
  • Poly(ethylene glycol)
  • Polymer therapeutics
  • Tumor angiogenesis
  • αβ integrin


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