Dual-Function Polymeric HPMA Prodrugs for the Delivery of miRNA

Zheng Hong Peng, Ying Xie, Yan Wang, Jing Li, David Oupicky

Research output: Contribution to journalArticle

6 Scopus citations

Abstract

An HPMA-based polymeric prodrug of a CXCR4 antagonist, AMD3465 (P-SS-AMD), was developed as a dual-function carrier of therapeutic miRNA. P-SS-AMD was synthesized by a copolymerization of HPMA with a methacrylamide monomer in which the AMD3465 was attached via a self-immolative disulfide linker. P-SS-AMD showed effective release of the parent AMD3465 drug following treatment with intracellular levels of glutathione (GSH). The AMD3465 was released in the cells and exhibited functional CXCR4 antagonism, demonstrated by inhibition of the CXCR4-mediated cancer cell invasion. Due to its cationic character, P-SS-AMD could form polyplexes with miRNA and mediate efficient transfection of miR-200c mimics to downregulate expression of a downstream target ZEB-1 in cancer cells. The combined P-SS-AMD/miR-200c polyplexes showed improved ability to inhibit cancer cell migration when compared with individual treatments. The reported findings validate P-SS-AMD as a dual-function delivery vector that can simultaneously deliver a therapeutic miRNA and function as a polymeric prodrug of CXCR4 antagonist.

Original languageEnglish (US)
Pages (from-to)1395-1404
Number of pages10
JournalMolecular Pharmaceutics
Volume14
Issue number5
DOIs
StatePublished - May 1 2017

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Keywords

  • CXCR4 antagonist
  • miRNA delivery
  • polymeric prodrug
  • polyplexes
  • self-immolative linker

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmaceutical Science
  • Drug Discovery

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