Cyclam-Modified PEI for Combined VEGF siRNA Silencing and CXCR4 Inhibition to Treat Metastatic Breast Cancer

Yiwen Zhou, Fei Yu, Feiran Zhang, Gang Chen, Kaikai Wang, Minjie Sun, Jing Li, David Oupicky

Research output: Contribution to journalArticle

12 Scopus citations

Abstract

Chemokine receptor CXCR4 plays an important role in cancer cell invasion and metastasis. Recent findings suggest that anti-VEGF therapies upregulate CXCR4 expression, which contributes to resistance to antiangiogenic therapies. Here, we report the development of novel derivatives of polyethylenimine (PEI) that effectively inhibit CXCR4 while delivering anti-VEGF siRNA. PEI was alkylated with different amounts of a CXCR4-binding cyclam derivative to prepare PEI-C. Modification with the cyclam derivatives resulted in a considerable decrease in cytotoxicity when compared with unmodified PEI. All the PEI-C showed significant CXCR4 antagonism and the ability to inhibit cancer cell invasion. Polyplexes of PEI-C prepared with siVEGF showed effective silencing of the VEGF expression in vitro. In vivo testing in a syngeneic breast cancer model showed promising antitumor and antimetastatic activity of the PEI-C/siVEGF polyplexes. Our data demonstrate the feasibility of using PEI-C as a carrier for simultaneous VEGF silencing and CXCR4 inhibition for enhanced antiangiogenic cancer therapies.

Original languageEnglish (US)
Pages (from-to)392-401
Number of pages10
JournalBiomacromolecules
Volume19
Issue number2
DOIs
StatePublished - Feb 12 2018

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ASJC Scopus subject areas

  • Bioengineering
  • Biomaterials
  • Polymers and Plastics
  • Materials Chemistry

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