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

结直肠癌（CRC）是美国癌症相关死亡的第二大原因。 大多数CRC患者有远处或区域转移，预后差。虽然免疫 检查点阻断（ICB）已证明对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， 大约95%的mCRC患者具有MMR熟练（pMMR）或MSI低病变。有一个 迫切需要能够使pMMR/MSI低的CRC敏感、改善对CRC的识别和呈现的方法。 肿瘤相关抗原，并激活T细胞增殖和与ICB协同组合的应答 以克服目前对mCRC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配位聚合物（NCP）。 NCPs通过金属离子与多齿配体的配位聚合而形成， 通过利用增强的渗透性和滞留效应在肿瘤组织中积累， 具有优于现有纳米治疗剂的几个优点。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模式 可以全身给药的NCP。 我们已经开发了OX/SN 38 NCP，其在核心中具有亲水性奥沙利铂（OX）前药，在核心中具有疏水性奥沙利铂前药。 壳上的SN 38前药。肿瘤靶向和活化的OX/SN 38显示出有效的抗癌作用 并与抗PD-L1抗体（αPD-L1）协同作用，用于CRC模型中的强效化学免疫治疗。我们 还开发了一种用于共同递送OX和2 '，3'-环GMP-AMP（cGAMP）激动剂的稳健NCP， 干扰素基因刺激因子（STING）对肿瘤的作用。OX/cGAMP显著延长了cGAMP在小鼠体内的半衰期。 循环和破坏肿瘤血管以增强肿瘤积聚。 提出的研究的总体目标是开发肿瘤靶向核-壳NCP，OX/CDN/Chol-D， 通过分别优化CDN和胆固醇缀合药物（Chol-D）， 和Chol-D引起肿瘤免疫原性细胞死亡（ICD），并释放CDN用于STING活化。 肿瘤微环境我们将阐明通过LDLR增强药物递送至肿瘤的机制- OX/CDN/Chol-D介导的内吞和肿瘤血管破坏，并评估其抗癌作用 在多种CRC模型中单独使用和与αPD-L1联合使用的疗效。通过制造免疫原性肿瘤 OX/CDN/Chol-D有望通过激活微环境，激活STING，并引发T细胞介导的细胞毒性， 将免疫学上“冷”的CRC肿瘤“热”化，与ICB协同组合以改善免疫治疗 的mCRC。我们在这个多学科项目上的密切合作有望确定一种新的三模态 纳米医学用于临床转化，以治疗预后不良的mCRC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.