Department of Chemistry, The University of Chicago, 929 E 57th St, Chicago, IL, 60637, USA.
Department of Chemistry, The University of Chicago, 929 E 57th St, Chicago, IL, 60637, USA; Department of Radiation and Cellular Oncology and Ludwig Center for Metastasis Research, The University of Chicago, 5758, S Maryland Ave, Chicago, IL, 60637, USA.
Biomaterials. 2023 Oct;301:122235. doi: 10.1016/j.biomaterials.2023.122235. Epub 2023 Jul 1.
The combination chemotherapy regimen FOLFIRINOX comprising folinic acid, 5-fluorouracil, irinotecan, and oxaliplatin is the first-line treatment for patients with advanced pancreatic cancer, but its use remains prohibitive for the majority of patients due to severe side effects. Here, we report a core-shell nanoscale coordination polymer (NCP) nanoparticle co-delivering a potent and synergistic combination of oxaliplatin, gemcitabine, and SN38 (OGS), for the treatment of pancreatic cancer in mouse models. OGS contains key synergistic components of FOLFIRINOX in a controllable drug ratio., It exhibited particle stability in blood circulation and enhanced deposition of the drugs in acidic tumor environments. In vitro, OGS showed superior cytotoxicity over free drug combinations and robust cytotoxic synergism among its three components. In vivo, OGS improved drug circulation, increased tumor deposition, and exhibited superior antitumor efficacy over the free drug combination in both subcutaneous and orthotopic pancreatic tumor models. OGS treatment achieved 75-91% tumor growth inhibition and prolonged mouse survival by 1.6- to 2.8-folds while minimizing systemic toxicities such as neutropenia, hepatotoxicity, and renal toxicity. This work uncovers a novel and clinically relevant nanomedicine strategy to co-deliver synergistic combination chemotherapies for difficult-to-treat cancers.
包含亚叶酸、5-氟尿嘧啶、伊立替康和奥沙利铂的 FOLFIRINOX 联合化疗方案是晚期胰腺癌患者的一线治疗方法，但由于严重的副作用，其应用仍然受到限制。在这里，我们报告了一种核壳纳米级配位聚合物（NCP）纳米粒子，用于协同递送奥沙利铂、吉西他滨和 SN38（OGS），用于治疗小鼠模型中的胰腺癌。OGS 包含 FOLFIRINOX 的关键协同成分，且药物比例可控。它在血液循环中表现出颗粒稳定性，并增强了药物在酸性肿瘤环境中的沉积。在体外，OGS 显示出优于游离药物组合的细胞毒性，并且其三种成分之间具有强大的细胞毒性协同作用。在体内，OGS 改善了药物循环，增加了肿瘤沉积，并在皮下和原位胰腺肿瘤模型中表现出优于游离药物组合的抗肿瘤疗效。OGS 治疗实现了 75-91%的肿瘤生长抑制，并将小鼠的存活时间延长了 1.6-2.8 倍，同时最大限度地减少了中性粒细胞减少、肝毒性和肾毒性等全身毒性。这项工作揭示了一种新的、有临床意义的纳米医学策略，用于协同递送达难治性癌症的联合化疗药物。
