Delivery of Anti-miRNA for Triple-Negative Breast Cancer Therapy Using RNA Nanoparticles Targeting Stem Cell Marker CD133

Hongran Yin, Gaofeng Xiong, Sijin Guo, Congcong Xu, Ren Xu, Peixuan Guo, Dan Shu

Research output: Contribution to journalArticlepeer-review

78 Scopus citations

Abstract

Triple-negative breast cancer (TNBC) is an aggressive disease with a short median time from relapse to death. The increased aggressiveness, drug resistance, disease relapse, and metastasis are associated with the presence of stem cells within tumors. Several stem cell markers, such as CD24, CD44, CD133, ALDH1, and ABCG2, have been reported, but their roles in breast cancer tumorigenesis remain unclear. Herein, we apply RNA nanotechnology to deliver anti-microRNA (miRNA) for TNBC therapy. The thermodynamically and chemically stable three-way junction (3WJ) motif was utilized as the scaffold to carry an RNA aptamer binding to CD133 receptor and a locked nuclei acid (LNA) sequence for miRNA21 inhibition. Binding assays revealed the specific uptake of the nanoparticles to breast cancer stem cells (BCSCs) and TNBC cells. Functional assays showed that cancer cell migration was reduced, miR21 expression was inhibited, and downstream tumor suppressor PTEN and PDCD4 expressions were upregulated. In vitro and in vivo studies revealed that these therapeutic RNA nanoparticles did not induce cytokine secretion. Systemic injection of these RNA nanoparticles in animal trial demonstrated high specificity in TNBC tumor targeting and high efficacy for tumor growth inhibition. These results revealed the clinical translation potential of these RNA nanoparticles for TNBC therapy. Yin et al. utilized a stable three-way junction (3WJ) motif as a scaffold, further functionalized with CD133 aptamer, anti-miR21, and Alexa647 fluorophore, for triple-negative breast cancer targeting and therapy. The multifunctional RNA nanoparticles were capable of inhibiting tumor growth in a mouse model with undetectable toxicity.

Original languageEnglish
Pages (from-to)1252-1261
Number of pages10
JournalMolecular Therapy
Volume27
Issue number7
DOIs
StatePublished - Jul 3 2019

Bibliographical note

Funding Information:
The research was supported by DOD awards (W81XWH-15-1-0052 to D.S. and R.X.)as well as NIH grants (R01EB019036, U01CA151648, and U01CA207946 to P.G. R21CA209045 to R.X. and D.S. R01CA207772, and R01CA215095 to R.X.). P.G.’s Sylvan G. Frank Endowed Chair position in Pharmaceutics and Drug Delivery is funded by the CM Chen Foundation.

Funding Information:
The research was supported by DOD awards ( W81XWH-15-1-0052 to D.S. and R.X.) as well as NIH grants ( R01EB019036 , U01CA151648 , and U01CA207946 to P.G., R21CA209045 to R.X. and D.S., R01CA207772 , and R01CA215095 to R.X.). P.G.’s Sylvan G. Frank Endowed Chair position in Pharmaceutics and Drug Delivery is funded by the CM Chen Foundation .

Publisher Copyright:
© 2019 The American Society of Gene and Cell Therapy

Keywords

  • CD133 aptamer
  • RNA nanoparticles
  • RNA nanotechnology
  • anti-miRNA
  • triple-negative breast cancer

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery

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