# Nanoparticle delivered miR-489 rejuvenates anthracycline-based chemotherapy

> **NIH NIH R21** · UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA · 2021 · $217,080

## Abstract

Abstract
 Triple-negative breast cancer (TNBC) comprises 15 to 20% of breast cancers and is the most
aggressive subtype with a significantly shorter median overall survival compared to other subtypes.
There are no targeted therapies for TNBC and only 10% of TNBC patients respond to immune therapy.
Thus, most of patients with TNBC still mainly depend on conventional chemotherapies, with doxorubicin
(Dox) as a commonly used one. The two crucial concerns with use of chemotherapies such as Dox are
severe toxicity and drug resistance. Extensive studies have unveiled many altered signaling pathways
that contribute to the development of Dox resistance. However, it is a daunting task to identify agents
that can target the diverse drug-resistant pathways simultaneously. Recently, synthetic miRNA mimics
or inhibitors have become attractive tools to battle cancer as a new type of therapies or to break drug
resistance because one microRNA can target multiple genes in multiple signaling pathways. Our recent
published data showed that miR-489 is lost in a majority of breast cancers especially TNBC. Loss of
miR-489 confers resistance to chemotherapies such as doxorubicin (Dox) and restoration of miR-489
reverses Dox resistance both in vitro and in vivo. Further mechanistic studies revealed that miR489
can inhibit Dox-induced cytoprotective autophagy, increase Dox localization in nucleus and potentiate
Dox-induced ATP release. Importantly, we developed a nanoparticle system to specifically deliver
miR489 to breast tumors. Based on these findings, we propose that nanoparticle delivered miR-489
can simultaneously modulate multiple pathways involved in cell proliferation, apoptosis, epithelial-
mesenchymal transition (EMT), autophagy and ER stress to enhance Dox-induced cell death and anti-
cancer immunity and therefore delay or reverse Dox resistance. Three specific aims are proposed.
SA1. To formulate tumor-targeting miR-489 nanoparticles and characterize the delivery efficiency and
toxicity both in vitro and in vivo. SA2. To test whether miR-489 synergizes with Dox to induce cell
death and reverses Dox-resistance using cell line and patient-derived xenograft (PDX) mouse models.
SA3. To investigate whether miR-489 enhances the efficacy of Dox treatment of PDX using humanized
mouse models. Overall, this study aims to develop miR-489 as a novel therapeutic agent to reverse
Dox resistance and thus enhance the efficacy of Dox-based chemotherapy.

## Key facts

- **NIH application ID:** 10167656
- **Project number:** 5R21CA252360-02
- **Recipient organization:** UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
- **Principal Investigator:** Hexin Chen
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $217,080
- **Award type:** 5
- **Project period:** 2020-06-01 → 2023-05-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10167656

## Citation

> US National Institutes of Health, RePORTER application 10167656, Nanoparticle delivered miR-489 rejuvenates anthracycline-based chemotherapy (5R21CA252360-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10167656. Licensed CC0.

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