# Development of Biodegradable Nanocarrier for Improved Co-delivery of PARPi and DNMTi

> **NIH NIH P20** · UNIVERSITY OF NEBRASKA MEDICAL CENTER · 2024 · $280,905

## Abstract

While PARP inhibitors like BMN673 (Talazoparib) have shown significant effectiveness in treating cancers 
with homologous recombination (HR) deficiency, their benefits are limited for HR-proficient cancers. The 
combination of a DNMT inhibitor (DNMTi) such as 5-azacytidine (AZA) with PARPi has been shown to 
enhance efficacy by inducing HR defects. However, the application of this combination is challenged by the 
poor bioavailability and the off-target toxicity of both drugs. Efficiently co-delivering PARPi and DNMTi via 
nanocarriers is complex due to their differing physicochemical properties and the challenge of achieving 
precise tumor targeting. Once entering biological fluids, most NPs acquire a protein corona that dictates 
their biological identity and behavior in the body, complicating the design of nanocarriers for predictable 
and enhanced tumor targeting. In our preliminary studies, we developed a small sized nanocarrier based 
on AZA-conjugated polymer that could efficiently load BMN673. The new formulation was more effective in 
suppressing tumor growth in PARPi-insensitive NSCLC tumor models compared to free drug combinations. 
PAZA nanocarrier demonstrated excellent tumor penetration due to a new mechanism of active targeting 
that involves the recruitment of fibronectin from serum proteins following systemic administration. However, 
the complexity of precisely controlling the protein corona, influenced by variables such as polymer structure 
and molecular weight, poses a significant challenge and impacts the nanocarrier's behavior in biological 
systems. In addition, the current PAZA carrier is non-biodegradable, which may accumulate in the body 
over time, raising concerns about its long-term safety. To address these issues, the first objective is to 
develop biodegradable bPAZA carriers and evaluate the impact of polymer structure on the protein corona 
composition. A detailed understanding of how NPs interact with serum proteins and the impact on 
biodistribution will allow for precise modulation of protein corona. The second objective focuses on 
conjugating cetuximab, a monoclonal antibody targeting EGFR, to a bPAZA carrier exhibiting minimal 
protein corona. By leveraging the benefits of cetuximab's dual role as a targeting agent and a therapeutic, 
the proposed work will provide a new AZA-based nanocarrier with improved specificity and efficiency for 
enhanced PARPi based synthetical lethal therapy.

## Key facts

- **NIH application ID:** 11170785
- **Project number:** 5P20GM121316-07
- **Recipient organization:** UNIVERSITY OF NEBRASKA MEDICAL CENTER
- **Principal Investigator:** Jingjing Sun
- **Activity code:** P20 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $280,905
- **Award type:** 5
- **Project period:** 2018-03-16 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11170785

## Citation

> US National Institutes of Health, RePORTER application 11170785, Development of Biodegradable Nanocarrier for Improved Co-delivery of PARPi and DNMTi (5P20GM121316-07). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/11170785. Licensed CC0.

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