Targeted delivery of MicroRNA125a-5p by engineered lipid nanoparticles for the treatment of HER2 positive metastatic breast cancer

Stephen L. Hayward, David M. Francis, Parviz Kholmatov, Srivatsan Kidambi

Research output: Contribution to journalArticle

23 Scopus citations

Abstract

MicroRNAs (miRNAs) are endogenous regulators of gene expression that play a pivotal role in biological processes spanning from global homeostasis to disease onset and progression. The ability to manipulate and induce cellular reequilibrium of deregulated miRNA expression profiles by inhibition of oncogenic miRNA or overexpression of tumor suppressor miRNA is a promising cancer strategy, but is currently hindered in application by the lack of nonviral delivery systems. Here we present a lipid nanoparticle (LNP) platform surface coated with Hyaluronic Acid (HA) for the delivery of mature tumor suppressor MicroRNA125a-5p to treat HER2 positive metastatic breast cancer. The delivery platform actively targets patient-derived metastatic breast cancer cells (21MT-1) isolated from the metastatic pleural effusion over normal breast tissue via an intrinsic HA-CD44 mediated endocytosis event, and has the ability to escape from the intracellular endolysosomal pathway for potent gene silencing. Knockdown of the HER2 proto-oncogene at the level of transcription and translation was achieved following HA-LNP mediated transfection with MicroRNA125a-5p. In addition, the PI3K/AKT and MAPK hyperactivated signaling pathways, cellular proliferation, and migration potential were also potently suppressed. Furthermore, the therapeutic efficacy of MicroRNA125a-5p by the HA-LNP platform was demonstrated to be significantly improved as compared to a commercial transfection reagent. This study highlights the therapeutic potential of MicroRNA125a-5p as a standalone treatment of HER2+ metastatic breast cancer via a translational nonviral delivery platform. These findings have major implications on future gene therapy regimens for breast cancer.

Original languageEnglish (US)
Pages (from-to)554-568
Number of pages15
JournalJournal of Biomedical Nanotechnology
Volume12
Issue number3
DOIs
StatePublished - Mar 2016

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Keywords

  • Breast Cancer
  • Gene Delivery
  • HER2 Targeting
  • Hyaluronic Acid
  • Lipid Nanoparticles
  • Liposomes
  • MicroRNA

ASJC Scopus subject areas

  • Bioengineering
  • Medicine (miscellaneous)
  • Biomedical Engineering
  • Materials Science(all)
  • Pharmaceutical Science

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