# Enhancing miRNA Therapeutics through Vehicle Free Delivery

> **NIH NIH R01** · PURDUE UNIVERSITY · 2024 · $386,127

## Abstract

PROJECT SUMMARY
Like the challenges and skepticism that faced the antibody therapeutics field over a decade ago, RNA
therapeutics is facing the same. And, like the antibody therapeutics field, we are beginning to realize the clinical
impact of RNA therapeutics amiss these challenges. This is most clearly highlighted with the recent approval of
two mRNA vaccines to prevent against SARS-CoV-2 and the first three FDA approved RNAi drugs targeted to
the liver. Unfortunately, RNA-based drugs targeted to cancer cells is lagging behind, even with countless years
of work that has revealed the power of using RNAi for treating oncological diseases. Lack of success in this
space is attributed to inability to deliver RNAi safely and effectively. A successful delivery agent requires multiple
features. First, the agent must deliver the RNA specifically to the intended cells. Second, the agent must have a
large therapeutic window, meaning that toxicity, if observed, should occur at doses that are orders of magnitude
higher than the therapeutic dose. Third, if delivery of the RNA is by way of a specific ligand and receptor pair, as
is the case herein, the RNA must successfully escape the endosome. Simply swelling the endosome is not
enough if noncovalent interactions between the ligand and the receptor cannot be disrupted. Fourth, the RNA
should include appropriate stabilizing modifications to increase intracellular half-life that will reduce dosing and
cost. Through hard work and dedication in this space, we have come up with an inclusive, easily synthesized,
intramolecular molecule that will achieve all of these essential features. Moreover, the ligand used to achieve
successful delivery is also being evaluated for imaging tumors localized in the central nervous system.
 The premise for this work is based on conjugating the tumor suppressive microRNA, miR-34a to 5-
methyltetrahydrofolate (5-MTHF), a ligand that is superior for the intended needs, in this case, release from the
receptor when an endosomal escape agent is present. Our preliminary data and strong scientific premise
supports our objective to i) advance 5-MTHF as a specific and non-toxic therapeutic ligand for delivery of
therapeutic miRNAs to triple negative breast cancer (TNBC) and ii) to characterize and prepare 5-MTHF-nigericin
conjugated to a fully modified version of miR-34a for clinical trial. To support these objectives, the following Aims
will be conducted: 1) To test the hypothesis that both in vivo and intracellular biodistribution of 5-MTHF
conjugates are superior to folate conjugates, and 2) To evaluate activity, efficacy, toxicity, pharmacokinetics,
dynamics, and combinatorial effects of 5-MTHF-nigericin conjugated to fully modified miR-34a in vivo. At the
completion of this work we will have the first an all-encompassing RNAi delivery vehicle that can deliver a
stabilized RNA to the intended cells, into the correct subcellular location, with limited toxicity for the treatment of
TNBC.

## Key facts

- **NIH application ID:** 10812030
- **Project number:** 2R01CA205420-06A1
- **Recipient organization:** PURDUE UNIVERSITY
- **Principal Investigator:** Andrea L Kasinski
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $386,127
- **Award type:** 2
- **Project period:** 2017-09-30 → 2029-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10812030

## Citation

> US National Institutes of Health, RePORTER application 10812030, Enhancing miRNA Therapeutics through Vehicle Free Delivery (2R01CA205420-06A1). Retrieved via AI Analytics 2026-09-23 from https://api.ai-analytics.org/grant/nih/10812030. Licensed CC0.

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