Wednesday, May 1, 2024
5/1/2024
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 (aPD-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 aPD-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.
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