Translational Modeling Identifies Synergy between Nanoparticle-Delivered miRNA-22 and Standard-of-Care Drugs in Triple-Negative Breast Cancer

Prashant Dogra, Javier Ruiz Ramírez, Joseph D Butner, Maria J Peláez, Caroline Chung, Anupama Hooda-Nehra, Renata Pasqualini, Wadih Arap, Vittorio Cristini, George A Calin, Bulent Ozpolat, Zhihui Wang

Research output: Contribution to journalArticlepeer-review

Abstract

PURPOSE: Downregulation of miRNA-22 in triple-negative breast cancer (TNBC) is associated with upregulation of eukaryotic elongation 2 factor kinase (eEF2K) protein, which regulates tumor growth, chemoresistance, and tumor immunosurveillance. Moreover, exogenous administration of miRNA-22, loaded in nanoparticles to prevent degradation and improve tumor delivery (termed miRNA-22 nanotherapy), to suppress eEF2K production has shown potential as an investigational therapeutic agent in vivo.

METHODS: To evaluate the translational potential of miRNA-22 nanotherapy, we developed a multiscale mechanistic model, calibrated to published in vivo data and extrapolated to the human scale, to describe and quantify the pharmacokinetics and pharmacodynamics of miRNA-22 in virtual patient populations.

RESULTS: Our analysis revealed the dose-response relationship, suggested optimal treatment frequency for miRNA-22 nanotherapy, and highlighted key determinants of therapy response, from which combination with immune checkpoint inhibitors was identified as a candidate strategy for improving treatment outcomes. More importantly, drug synergy was identified between miRNA-22 and standard-of-care drugs against TNBC, providing a basis for rational therapeutic combinations for improved response CONCLUSIONS: The present study highlights the translational potential of miRNA-22 nanotherapy for TNBC in combination with standard-of-care drugs.

Original languageEnglish (US)
JournalPharmaceutical Research
Early online dateMar 16 2022
DOIs
StateE-pub ahead of print - Mar 16 2022

Keywords

  • allometry
  • cancer treatment
  • mathematical modeling
  • microRNA
  • pharmacokinetics and pharmacodynamics
  • precision medicine
  • tumor-immune interaction

ASJC Scopus subject areas

  • Biotechnology
  • Molecular Medicine
  • Pharmacology
  • Pharmaceutical Science
  • Organic Chemistry
  • Pharmacology (medical)

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