Shanghai Engineering Research Center of Nano-Biomaterials and Regenerative Medicine, College of Chemistry, Chemical Engineering and Biotechnology, Donghua University, Shanghai 201620, PR China.
Department of Cardiovascular Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201600, PR China.
Acta Biomater. 2022 Sep 1;149:334-346. doi: 10.1016/j.actbio.2022.06.041. Epub 2022 Jun 30.
Immunotherapy has been used for cancer treatment, while it faces the common dilemmas of low therapeutic efficacy and serious immunotoxicity. In this study, we report the construction of a tumor microenvironment and near-infrared (NIR) light dual-responsive prodrug hydrogel for cancer synergistic immunotherapy in a more effective and safe manner. Such prodrug hydrogels were in-situ formed via calcium-induced gelation of alginate solution containing protoporphyrin IX (PpIX)-modified iron oxide (FeO) nanoparticles and programmed death ligand 1 antibody (aPD-L1) prodrug nanoparticles crosslinked by reactive oxygen species (ROS)-responsive linkers. PpIX served as a photosensitizer to produce singlet oxygen (O) under NIR laser irradiation for photodynamic therapy (PDT), and FeO nanoparticles mediated chemodynamic therapy (CDT) to generate hydroxyl radical (·OH) via Fenton reaction in the tumor microenvironment. In view of the cumulative actions of PDT and CDT, amplified ROS was generated to not only induce immunogenic cell death (ICD), but also destroy ROS-responsive linkers to achieve on-demand release of aPD-L1 from prodrug nanoparticles. Boosted antitumor immunity was elicited in tumor-bearing mice due to the aPD-L1-mediated immune checkpoint blocking. As a result, the prodrug hydrogel-based synergistic immunotherapy could almost treat bilateral tumors and prevent lung and liver metastasis using 4T1 tumor mouse models. This study thus offers a dual-responsive prodrug hydrogel platform for precision cancer immunotherapy. STATEMENT OF SIGNIFICANCE: Via calcium-induced gelation of alginate, we constructed a prodrug hydrogel with tumor microenvironment and near-infrared light dual-responsive action for synergistic cancer immunotherapy. Such hydrogels can achieve on-demand release of aPD-L1 upon photoactivation in the tumor microenvironment. Through mediating photodynamic and chemodynamic therapy, the prodrug hydrogels can induce enhanced immunogenic cell death and synergistically improve the efficacy of aPD-L1-mediated immune checkpoint blocking. The prodrug hydrogel-based synergistic therapy almost deracinates the primary and distant tumors, and prevents lung and liver metastasis in tumor mouse models.
免疫疗法已被用于癌症治疗，但它面临着治疗效果低和严重免疫毒性的常见难题。在这项研究中，我们报告了一种构建肿瘤微环境和近红外（NIR）光双重响应前药水凝胶的方法，以更有效和安全的方式进行癌症协同免疫治疗。这种前药水凝胶是通过含有原卟啉 IX（PpIX）修饰的氧化铁（FeO）纳米粒子的藻酸钠溶液在钙离子诱导下原位形成的，其中包含程序性死亡配体 1 抗体（aPD-L1）前药纳米粒子通过活性氧（ROS）响应性连接物交联。PpIX 可在近红外激光照射下产生单线态氧（O）作为光动力治疗（PDT）的光敏剂，而 FeO 纳米粒子通过在肿瘤微环境中发生芬顿反应介导化学动力学治疗（CDT）产生羟基自由基（·OH）。鉴于 PDT 和 CDT 的累积作用，产生了放大的 ROS，不仅诱导免疫原性细胞死亡（ICD），而且还破坏 ROS 响应性连接物以实现 aPD-L1 从前药纳米颗粒的按需释放。由于 aPD-L1 介导的免疫检查点阻断，荷瘤小鼠中引发了增强的抗肿瘤免疫。结果，基于前药水凝胶的协同免疫疗法几乎可以使用 4T1 肿瘤小鼠模型治疗双侧肿瘤并预防肺和肝转移。因此，该研究为精确癌症免疫治疗提供了一种双重响应前药水凝胶平台。
通过藻酸钠的钙离子诱导凝胶化，我们构建了一种具有肿瘤微环境和近红外光双重响应作用的前药水凝胶，用于协同癌症免疫治疗。这种水凝胶可以在肿瘤微环境中光激活后按需释放 aPD-L1。通过介导光动力和化学动力学治疗，前药水凝胶可以诱导增强的免疫原性细胞死亡，并协同提高 aPD-L1 介导的免疫检查点阻断的疗效。基于前药水凝胶的协同治疗几乎根除了原发性和远处肿瘤，并预防了肿瘤小鼠模型中的肺和肝转移。
