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

用于转移性结直肠癌化疗免疫治疗的肿瘤靶向多模态纳米配位聚合物

基本信息

批准号：
10639649
负责人：
Wenbin Lin
金额：
$ 46.68万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-03-01 至 2028-02-29
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10639649
关键词：
Address Agonist Antigen Presentation Antigens Binding Biodistribution Cancer Etiology Cancer Model Cell-Mediated Cytolysis Cessation of life Cholesterol Circulation Clinical Trials Collaborations Colorectal Cancer Colorectal Neoplasms Combination Drug Therapy Cyclic GMP Deposition Development Dinucleoside Phosphates Disseminated Malignant Neoplasm Distant Distant Metastasis Drug Delivery Systems Drug Kinetics Epithelial Cells Exhibits Gene Activation Goals Half-Life Hybrids Hydrophobicity Immune Immuno-Chemotherapy Immunologic Memory Immunologics Immunotherapy In Vitro Interferon Type I Ions Lesion Ligands Low Density Lipoprotein Receptor Low-Density Lipoproteins Mediating Metals Methods Microsatellite Instability Mismatch Repair Mismatch Repair Deficiency Modality Modeling Molecular Morbidity - disease rate Mus Neoplasm Metastasis Paclitaxel Pathway interactions Patients Pattern Periodicity Permeability Pharmaceutical Preparations Polymers Pre-Clinical Model Prodrugs Prognosis Regimen Research Resistance Signal Transduction Solid Stimulator of Interferon Genes Survival Rate T-Cell Activation T-Cell Proliferation T-Lymphocyte Therapeutic Index Toxic effect Tumor Antigens Tumor Immunity Tumor Tissue anti-PD-L1 anti-PD-L1 antibodies anti-cancer antitumor effect cancer cell cancer therapy chemotherapy clinical candidate clinical care clinical translation colon cancer patients cytokine docetaxel effective therapy hydrophilicity immune checkpoint blockade immunogenic immunogenic cell death improved in vivo metastatic colorectal mortality mouse model multidisciplinary multimodality nanomedicine nanoparticle nanoscale nanoshell nanotherapeutic novel novel therapeutics overexpression oxaliplatin particle polymerization receptor mediated endocytosis response side effect standard of care subcutaneous synergism tool transcriptome sequencing tumor tumor microenvironment uptake

项目摘要

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.

项目摘要：结直肠癌（CRC）是美国与癌症相关死亡的第二大原因大多数CRC患者具有远处或区域转移，预后不良。虽然免疫检查点封锁（ICB）已显示出对MCRC患者的有利反应和生存益处不匹配维修（MMR）缺陷或微卫星不稳定性（MSI） - 高肿瘤，它不受益受大约95％的MMR促进（PMMR）或MSI-LOW病变的MCRC患者。有一个迫切需要可以感觉到PMMR/MSI-LOW CRC的方法，改善识别和表现与肿瘤相关的抗原，并激活T细胞增殖和与ICB协同组合的反应为了克服MCRC患者的临床护理中当前局限性。我们开创了用于癌症治疗的纳米级配位聚合物（NCP）的开发。通过金属离子和多脱牙配体之间的协调聚合形成，NCPS优先通过利用增强的渗透性和保留效应，积聚在肿瘤组织中比现有的纳米疗法具有多个优势。我们研究的长期目标是建立通过开发和表征转移性结直肠癌的新治疗范式可以系统地交付的NCP。我们已经在核心中开发了具有亲水性奥沙利铂（OX）前药的OX/SN38 NCP和疏水性前药 SN38在外壳上前药。靶向肿瘤和激活的OX/SN38表现出有效的抗癌作用并与抗PD-L1抗体（αPD-L1）协同作用，用于CRC模型中强的化学免疫疗法。我们还为OX和2'，3'Cycle GMP – Amp（CGAMP）激动剂开发了强大的NCP 干扰素基因（STING）的刺激剂。 OX/CGAMP显着延长了CGAMP的半衰期循环和破坏肿瘤血管，以增强肿瘤的积累。拟议的研究的总体目标是开发针对肿瘤的核心壳NCP，OX/CDN/CHOL-D，通过优化CDN和胆固醇偶联的药物（CHOL-D），用于OX的共递送并引起肿瘤免疫原性细胞死亡（ICD）和CDN释放用于在肿瘤微环境。我们将通过LDLR-阐明药物递送到肿瘤的机制 OX/CDN/CHOL-D介导的内吞作用和肿瘤脉管系统破坏并评估其抗癌在多个CRC模型中，单独并与αPD-L1结合使用。通过创建免疫原性肿瘤微环境，激活刺痛和引发T细胞介导的细胞毒性，OX/CDN/CHOL-D有望在免疫学上“冷” CRC肿瘤“热”以与ICB协同组合，以改善免疫疗法 MCRC。我们在这个多学科项目上的密切合作承诺可以识别一种新颖的三模式用于治疗预后不良的MCRC患者的纳米医学素。