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

• 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
• 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

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) 是美国癌症相关死亡的第二大原因。 大多数CRC患者虽然具有免疫力，但仍存在远处或区域转移，预后较差。 检查点封锁 (ICB) 已证明对转移性结直肠癌 (mCRC) 患者有良好的反应和生存益处 对于错配修复（MMR）缺陷或微卫星不稳定性（MSI）高的肿瘤，它没有益处 大约 95% 的 mCRC 患者具有 MMR 充分 (pMMR) 或 MSI 低病变。 迫切需要能够敏化 pMMR/MSI-low CRC、提高对 pMMR/MSI-low CRC 的识别和呈现的方法 肿瘤相关抗原，并激活T细胞增殖和反应，与ICB协同组合 克服目前转移性结直肠癌患者临床护理的局限性。 我们率先开发了用于癌症治疗的纳米级配位聚合物 (NCP)。 NCPs由金属离子和多齿配体之间的配位聚合形成 利用增强的渗透性和滞留效应在肿瘤组织中积累， 与现有纳米疗法相比具有多种优势 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例 可以系统地交付的 NCP。 我们开发了 OX/SN38 NCP，其核心为亲水性奥沙利铂 (OX) 前药，疏水性为 外壳上的 SN38 前药被证明具有强大的抗癌作用。 并与抗 PD-L1 抗体 (αPD-L1) 协同作用，在 CRC 模型中进行强效化学免疫治疗。 还开发了一种强大的 NCP，用于 OX 和 2’,3’-环 GMP-AMP (cGAMP) 激动剂的共同递送 OX/cGAMP 的肿瘤干扰素基因刺激剂 (STING) 显着延长了 cGAMP 的半衰期。 循环并破坏肿瘤脉管系统以增强肿瘤积累。 拟议研究的总体目标是开发一种肿瘤靶向核壳NCP，OX/CDN/Chol-D， 通过分别优化 CDN 和胆固醇结合药物 (Chol-D)，共同递送 OX 和 Chol-D 导致肿瘤免疫原性细胞死亡 (ICD) 并释放 CDN 以激活 STING 我们将阐明通过 LDLR-增强药物递送至肿瘤的机制。 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作用 通过创建免疫原性肿瘤，单独或与 αPD-L1 联合使用可在多种 CRC 模型中发挥功效。 OX/CDN/Chol-D 有望改善微环境、激活 STING 并引发 T 细胞介导的细胞毒性 将免疫“冷”CRC肿瘤“热”与ICB协同组合以改善免疫治疗 我们在这个多学科项目上的密切合作有望确定一种新颖的三模式。 纳米医学用于临床转化以治疗预后不良的转移性结直肠癌患者。