# Bottlebrush polymer prodrugs for targeted delivery of combination therapies and in vivo imaging of pharmacological response

> **NIH NIH R01** · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · 2024 · $566,131

## Abstract

ABSTRACT:
Pancreatic ductal adenocarcinoma (PDA) is a lethal disease with few effective treatments. The poor efficacy of
current therapies including immune checkpoint inhibitors (ICIs) is partly attributed to the characteristic
fibroinflammatory desmoplastic tumor microenvironment. Thus, strategies that overcome these stromal barriers
have the potential to profoundly improve therapeutic outcomes in PDA. Towards this end, epigenetic therapies
that broadly rewire cellular gene expression programs represent a promising approach for targeting PDA stromal
barriers. Preliminary studies with inhibitors of Bromodomain and Extra-Terminal domain (BET) proteins, whose
recognition of enhancer and super-enhancers drive cell-specific function, reveal a potent loss of
immunosuppressive programs within multiple stromal cell populations as well as tumor cells. In addition, the
clinical BET inhibitor OTX-015 (OTX) synergized with otherwise ineffective αPD-L1 immune checkpoint inhibition
to promote intra-tumoral cytotoxic T cell activation and decrease PDA tumor burden. However, OTX negatively
impacts T cell priming in secondary lymphoid tissue and long-term treatment is limited by systemic toxicities. To
overcome these limitations, this proposal will develop bottlebrush polymer prodrug (BPDs) to selectively deliver
drug cargoes to PDA tumors. BPDs are small, cylindrical macromolecules with multiple conjugated drugs within
their cores. This unique architecture enables improved tissue penetration and predictable properties independent
of drug composition, while molecular linkers facilitate highly selective drug release in target tissues. In Aim 1, the
ability of OTX-BPD conjugates incorporating cleavable linkers to selectively deliver drugs to tumors will be
evaluated in clinically relevant PDA mouse models. Subsequently, the ability of lead OTX-BPDs to synergize
with αPD-L1 will be determined in both short-term intervention and long-term survival studies. The therapeutic
utility of conjugating multiple drugs to BPDs will be determined in Aim 2. Specifically, chemotherapeutics found
to synergize with OTX as free drugs will be conjugated to OTX-BPDs, and the abilities of these multidrug laden
BPDs to reduce tumor growth and enhance anti-tumor immunity in combination with αPD-L1 will be determined
in PDA mouse models. In parallel, the therapeutic benefits of actively targeting these multidrug-laden BPDs by
conjugating to antibodies that recognize PDA cancer cell proteins will be assessed. In addition, the optimal ratio
of drugs conjugated to individual BPDs to achieve maximal efficacy will be established, which will be distinct
from free drugs. In combination, the development of targeted multidrug-laden BPDs will promote rational
combination therapies that leverage both epigenetic- and chemo-therapies to potentiate immune checkpoint
inhibitors. In the third aim, BPD reporters for drug-induced apoptosis and cytotoxic T cell activity will be developed
by incorporating m...

## Key facts

- **NIH application ID:** 10754275
- **Project number:** 5R01CA220468-07
- **Recipient organization:** MASSACHUSETTS INSTITUTE OF TECHNOLOGY
- **Principal Investigator:** Jeremiah Allen Johnson
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $566,131
- **Award type:** 5
- **Project period:** 2017-09-13 → 2027-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10754275

## Citation

> US National Institutes of Health, RePORTER application 10754275, Bottlebrush polymer prodrugs for targeted delivery of combination therapies and in vivo imaging of pharmacological response (5R01CA220468-07). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10754275. Licensed CC0.

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