# Therapeutic miRNA Modulation of Hepatocellular Carcinoma Using Ultrasound Guided Drug Delivery

> **NIH NIH R01** · STANFORD UNIVERSITY · 2020 · $622,615

## Abstract

Hepatocellular carcinoma (HCC) is a common and deadly cancer of the liver with increasing incidence in the
United Stated. New therapeutic strategies are critically needed as current treatment options are limited,
particularly for those who are resistant to doxorubicin and other chemotherapies. MicroRNAs (miRNAs) are
potent gene expression regulators that when aberrantly expressed, play a profound role in cancer development
and progression. Two miRNAs, miRNA-122 and miRNA-21, have been identified to play a major role in tumor
growth, metastasis and chemoresistance in HCC. Therapeutic restoration of both miRNAs functions by
supplementing oligonucleotide mimics of endogenous miRNA-122 and inhibiting overexpressed miRNA-21 with
antisense-miR-21 (antimiR-21) has the potential to not only slow HCC growth and metastasis, but also sensitize
these tumors to doxorubicin. A key challenge, however, is the ability to deliver these agents homogenously and
with high efficiency into tumor cells in vivo. Using an ultrasound (US) and microbubble (MB) mediated drug
delivery platform, we have recently demonstrated for the first time that therapeutic miRNAs can be successfully
delivered into HCC in mice in vivo when the miRNAs were loaded in an FDA-approved poly(lactic-co-glycolic
acid)-nanoparticle (PLGA-NP). The putative key mechanism to US and MB mediated delivery is the enhanced
vascular permeability caused by acoustic cavitation. However, to achieve efficient cancer drug delivery therapy
with minimal recurrence rates from insufficiently treated regions, a spatially homogeneous delivery pattern in the
tumors is critical. We hypothesize that a homogeneous delivery pattern of miRNA-122 and antimiR-21 can be
achieved when cavitation is successfully induced in the entire tumor volume, resulting in strong direct anticancer
effects and sensitizing HCC cells to doxorubicin chemotherapy. We will develop and test a new motion-
compensated US-guided drug delivery platform with a real-time passive cavitation-imaging-based quantitative
feedback algorithm implemented on the US system in the tumor volume. Guided by this imaging roadmap,
adjustment of several treatment parameters will be possible in real-time during the treatment to ensure
homogeneous and efficient therapeutic miRNA delivery with favorable long-term treatment effects in HCC.
Furthermore, we will assess any immunomodulatory effects of our treatment approach in a syngeneic HCC
model in immunocompetent mice. Also, as a next step towards clinical translation, we will move this therapeutic
approach from small to a larger animals (rabbits) and will combine it with transcatheter hepatic arterial
administration to approximate current clinical liver-directed therapies. The successful completion will pave the
way for a novel genetic reprogramming approach for treating doxorubicin-resistant HCC that targets aberrantly
expressed miRNA and implies synergistic effects with conventional chemotherapy such as doxorubicin.
Thera...

## Key facts

- **NIH application ID:** 9893823
- **Project number:** 5R01CA209888-04
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Jeremy Dahl
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $622,615
- **Award type:** 5
- **Project period:** 2017-04-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9893823

## Citation

> US National Institutes of Health, RePORTER application 9893823, Therapeutic miRNA Modulation of Hepatocellular Carcinoma Using Ultrasound Guided Drug Delivery (5R01CA209888-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9893823. Licensed CC0.

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