College of Chemistry & Environmental Science, Chemical Biology Key Laboratory of Hebei Province, Analytical Chemistry Key Laboratory of Hebei Province, Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of the Ministry of Education, Hebei University, Baoding 071002, PR China.
College of Chemistry & Environmental Science, Chemical Biology Key Laboratory of Hebei Province, Analytical Chemistry Key Laboratory of Hebei Province, Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of the Ministry of Education, Hebei University, Baoding 071002, PR China.
Biomaterials. 2017 Apr;122:23-33. doi: 10.1016/j.biomaterials.2017.01.017. Epub 2017 Jan 11.
Tumor-associated antigens (TAAs)-loaded nanoparticles are able to be actively internalized by antigen-presenting cells (APCs) and have shown promising potential in cancer immunotherapy. However, current TAAs delivery strategy exhibits limitations of complicated synthesis process, low loading efficiency and inefficient CD8 cytotoxic T lymphocyte activation leading to unsatisfactory therapeutic effect. Thus, the construction of novel TAAs-delivery systems for enhanced cancer therapy is highly desirable. In this work, we fabricated a very simple yet powerful antigens-delivery system for cancer immunotherapy based-on pH-responsive metal-organic frameworks (MOFs) with size about 30 nm. TAAs can be loaded into MOFs in the one-pot synthesis process and released with the degradation of MOFs in the acidic environment of endo/lysosome as the result of relatively labile metal-ligand bonds. The endosomolytic nanoparticles would facilitate protein antigens escape from endo/lysosome and optimal for enhancing antigen cross-presentation. Furthermore, the introduction of immunostimulatory unmethylated cytosine-phosphate-guanine oligonucleotide (CpG) through Watson-Crick base pairing would further enhance CD8 cytotoxic T lymphocyte responses. We demonstrated that the method to co-delivery antigens and immunostimulatory molecules was very simple, convenient and effective and showed no obvious toxicity both in vitro and in vivo. This method gave a high antigens-loading capacity and the maximal antigen encapsulating efficiency was about 55% (w/w). Additionally, the pH-responsive co-delivery system exerted enhanced antitumor outcome (about 100% survival) in B16-OVA melanoma cancers in vivo. Furthermore, we confirmed that this high rating of therapeutic effect was attributed to the recruitment of tumor-killing immunocyte. This work demonstrates the ability of pH-responsive, endosomolytic MOFs to induce strong cellular immune responses for cancer therapy by co-delivery of CpG ODN and antigens.
肿瘤相关抗原（TAA）负载的纳米颗粒能够被抗原呈递细胞（APC）主动内化，并在癌症免疫治疗中显示出有前途的潜力。然而，目前的 TAA 传递策略存在合成过程复杂、载药效率低、CD8 细胞毒性 T 淋巴细胞激活效率低等局限性，导致治疗效果不理想。因此，构建新型 TAA 传递系统以增强癌症治疗具有很高的需求。在这项工作中，我们基于尺寸约为 30nm 的 pH 响应型金属有机骨架（MOFs）构建了一种非常简单但功能强大的癌症免疫治疗用抗原传递系统。TAA 可以在一锅合成过程中被加载到 MOFs 中，并在酸性环境下通过 MOFs 的降解而释放，这是由于相对不稳定的金属配体键。溶酶体的内裂解纳米颗粒将促进蛋白质抗原从内体/溶酶体中逃逸，并优化抗原交叉呈递。此外，通过 Watson-Crick 碱基配对引入免疫刺激性非甲基化胞嘧啶-磷酸-鸟嘌呤寡核苷酸（CpG）将进一步增强 CD8 细胞毒性 T 淋巴细胞反应。我们证明了共传递抗原和免疫刺激性分子的方法非常简单、方便和有效，并且在体外和体内均没有明显的毒性。该方法具有较高的抗原载药能力，最大抗原包封效率约为 55%（w/w）。此外，pH 响应型共传递系统在体内 B16-OVA 黑色素瘤癌症中表现出增强的抗肿瘤效果（约 100%的存活率）。此外，我们证实这种高治疗效果归因于杀伤肿瘤免疫细胞的募集。这项工作证明了 pH 响应性、溶酶体裂解的 MOFs 通过共传递 CpG ODN 和抗原来诱导强烈的细胞免疫反应以用于癌症治疗的能力。
