# In Situ Albumin Binding siRNAs for Triple Negative Breast Cancer Tumor Penetration and Molecularly Targeted Therapy

> **NIH NIH R01** · VANDERBILT UNIVERSITY · 2022 · $117,567

## Abstract

Cancer nano-formulations for delivery of small molecule drugs are limited by the ability to target only ~10%
of the genome. RNAi molecules can, in theory, be designed against any gene of interest, but siRNA use in clinical
oncology faces delivery barriers such as nuclease degradation, rapid renal clearance, poor distribution into tumor
tissues, and poor cell membrane penetration. To overcome these challenges, most RNAi therapies focus on
synthetic lipo- and poly-plex nano-formulations. Unfortunately, while these technologies typically achieve very
high delivery into the liver, high-penetrance siRNA tumor delivery remains elusive.
 The overarching goal of this project is to develop siRNA chemical modifications that provide potent, safe,
tumor-penetrating, and molecularly targeted nano-therapeutics against currently undruggable tumor drivers. The
approach builds upon our recently published proof of principle siRNA molecules end-modified through a PEG45
linker with a diacyl lipid (siRNA-EG45<L2), which forms a nano-complex with albumin (alb-NC) in situ following
intravenous injection. This albumin “hitchhiking” siRNA-EG45<L2 enhances siRNA pharmacokinetic properties, is
very safe, provides natural tumor tropism, and increases tumor delivery level, homogeneity of tumor delivery,
and tumor:liver delivery ratio compared to conventional nano-polyplexes formed with in vivo-jetPEI (PEI-NPs).
The alb-NCs especially outperformed PEI-NPs for accumulating within challenging patient derived xenograft
(PDX) tumors that have reduced access to delivery by the enhanced permeability and retention (EPR) effect.
 The specific goal of this proposal is to further explore and optimize siRNA chemical modifications for in
situ formation of effective alb-NCs. We will benchmark new candidates against conventional nano-formulations
in simple (xenograft), immune-competent (allograft) and rigorous (PDX and spontaneous) tumor models. This
platform will be validated for silencing of the oncogene myeloid cell leukemia 1 (Mcl-1) to treat triple negative
breast cancer (TNBC). Mcl-1 is a vetted target with relevance in a broad range of cancers, supporting its use for
proof-of-concept. Furthermore, TNBC is a highly aggressive clinical breast cancer subtype with few treatment
options. TNBC patients are currently relegated to chemotherapies, and do not typically benefit from molecularly-
targeted therapies.
 This project is uniquely accessible by our multi-PI interdisciplinary team with bioengineering expertise in
intracellular biologic drug delivery nanotechnologies (Duvall), chemical synthesis (Uddin), analysis of noncoding
RNA transport on serum components (Vickers), Mcl-1 pathway modulation and analysis (Cook), and cutting
edge preclinical models, including PDX, for testing experimental therapies (Brantley-Sieders). Our basic
science expertise will be supplemented by consultation with Dr. Ingrid Mayer, a medical oncologist involved in
breast cancer clinical trials at Vanderbilt. Th...

## Key facts

- **NIH application ID:** 10596246
- **Project number:** 3R01CA260958-02S1
- **Recipient organization:** VANDERBILT UNIVERSITY
- **Principal Investigator:** Rebecca Sara Cook
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $117,567
- **Award type:** 3
- **Project period:** 2021-07-05 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10596246

## Citation

> US National Institutes of Health, RePORTER application 10596246, In Situ Albumin Binding siRNAs for Triple Negative Breast Cancer Tumor Penetration and Molecularly Targeted Therapy (3R01CA260958-02S1). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10596246. Licensed CC0.

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