# Tumor-Targeted Multimodality Nanoscale Coordination Polymers for Chemo-Immunotherapy of Metastatic Colorectal Cancer

> **NIH NIH R01** · UNIVERSITY OF CHICAGO · 2024 · $443,479

## Abstract

Project Summary: Colorectal cancer (CRC) is the second leading cause of cancer-related deaths in the U.S.
The majority of CRC patients have distant or regional metastasis and a poor prognosis. Although immune
checkpoint blockade (ICB) has demonstrated favorable responses and survival benefits for mCRC patients
with mismatch repair (MMR)-deficient or microsatellite instability (MSI)-high tumors, it does not benefit
approximately 95% of mCRC patients who have MMR-proficient (pMMR) or MSI-low lesions. There is an
urgent need for methods that can sensitize pMMR/MSI-low CRC, improve recognition and presentation of
tumor-associated antigens, and activate T-cell proliferation and responses for synergistic combination with ICB
to overcome current limitations in clinical care for mCRC patients.
 We have pioneered the development of nanoscale coordination polymers (NCPs) for cancer therapy.
Formed by coordination polymerization between metal ions and polydentate ligands, NCPs preferentially
accumulate in tumor tissues by taking advantage of the enhanced permeability and retention effect and
possess several advantages over existing nanotherapeutics. The long-term goal of our research is to establish
a new treatment paradigm for metastatic colorectal cancer through the development and characterization of
NCPs that can be delivered systemically.
 We have developed OX/SN38 NCP with a hydrophilic oxaliplatin (OX) prodrug in the core and a hydrophobic
SN38 prodrug on the shell. Tumor-targeted and -activated OX/SN38 demonstrated potent anticancer effect
and synergized with an anti-PD-L1 antibody (αPD-L1) for strong chemo-immunotherapy in CRC models. We
have also developed a robust NCP for the co-delivery of OX and 2’,3’-cyclic GMP–AMP (cGAMP) agonist of
stimulator of interferon genes (STING) to tumors. OX/cGAMP significantly prolonged the half-life of cGAMP in
circulation and disrupted tumor vasculatures to enhance tumor accumulation.
 The overall goal of the proposed studies is to develop a tumor-targeted core-shell NCP, OX/CDN/Chol-D,
through the optimization of CDN and cholesterol-conjugated drug (Chol-D) separately, for the co-delivery of OX
and Chol-D to cause tumor immunogenic cell death (ICD) and the release of CDN for STING activation in the
tumor microenvironment. We will elucidate the mechanisms of enhanced drug delivery to tumors via LDLR-
mediated endocytosis and tumor vasculature disruption by OX/CDN/Chol-D and evaluate its anticancer
efficacy alone and in combination with αPD-L1 in multiple CRC models. By creating an immunogenic tumor
microenvironment, activating STING, and eliciting T-cell mediated cytotoxicity, OX/CDN/Chol-D promises to
turn immunologically “cold” CRC tumors “hot” for synergistic combination with ICB to improve immunotherapy
of mCRC. Our close collaborations on this multidisciplinary project promise to identify a novel tri-modality
nanomedicine for clinical translation to treat mCRC patients with a poor prognosis.

## Key facts

- **NIH application ID:** 10795061
- **Project number:** 5R01CA279802-02
- **Recipient organization:** UNIVERSITY OF CHICAGO
- **Principal Investigator:** Wenbin Lin
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $443,479
- **Award type:** 5
- **Project period:** 2023-03-01 → 2028-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10795061

## Citation

> US National Institutes of Health, RePORTER application 10795061, Tumor-Targeted Multimodality Nanoscale Coordination Polymers for Chemo-Immunotherapy of Metastatic Colorectal Cancer (5R01CA279802-02). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10795061. Licensed CC0.

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