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

项目摘要：结直肠癌(CRC)是美国癌症相关死亡的第二大原因。 大多数结直肠癌患者有远处或区域转移，预后较差。虽然免疫 检查点阻断(ICB)已显示出对mCRC患者的良好反应和生存益处。 对于错配修复(MMR)缺陷或微卫星不稳定性(MSI)高的肿瘤，它没有好处 大约95%的mCRC患者具有MMR熟练(PMMR)或MSI低损害。有一个 迫切需要能够提高pMMR/MSI敏感性的方法-低CRC，改善对 肿瘤相关抗原，并激活T细胞增殖和与ICB协同结合的反应 以克服目前临床治疗多发性结直肠癌患者的局限性。 我们率先开发了用于癌症治疗的纳米配位聚合物(NCPs)。 由金属离子与多齿配体配位聚合而成，优先 通过利用增强的渗透性和滞留效应在肿瘤组织中积聚 拥有比现有纳米疗法更多的优势。我们研究的长期目标是建立 一种新的转移性结直肠癌治疗方案 可以有系统地交付的NCP。 我们研制了以奥沙利铂(OX)为核心的亲水性前药和疏水的OX/SN38 NCP 壳层上的SN38前药。肿瘤靶向和激活的OX/SN38显示出强大的抗癌作用 并与抗PD-L1抗体(αPD-L1)协同用于结直肠癌模型的强化学免疫治疗。我们 我们还开发了一种用于OX和2‘，3’-环GMP-AMP(CGAMP)激动剂(CGAMP)共递送的强大NCP 干扰素基因刺激物(刺激物)对肿瘤的作用。OX/cGAMP显著延长cGAMP在小鼠体内的半衰期 并破坏肿瘤血管，促进肿瘤聚集。 拟议研究的总体目标是开发一种肿瘤靶向的核壳NCP，OX/CDN/Chol-D， 通过对CDN和胆固醇偶联药物(Chol-D)的优化，实现了OX的联合给药 和Chol-D导致肿瘤免疫原性细胞死亡(ICD)，并释放CDN用于刺激性激活 肿瘤微环境。我们将阐明通过LDLR增强肿瘤药物输送的机制- OX/CDN/Chol-D介导的内吞作用和肿瘤血管破坏及其抗癌作用 在多种结直肠癌模型中单独和联合使用αPD-L1的疗效。通过制造一种免疫原性肿瘤 微环境，激活刺痛，并诱导T细胞介导的细胞毒作用，OX/CDN/Chol-D承诺 在免疫上使结直肠癌变冷为热，与ICB协同提高免疫治疗水平 Mcrc的。我们在这个多学科项目上的密切合作承诺确定一种新的三种模式 纳米药物用于临床翻译治疗预后不良的多发性结直肠癌患者。

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.