Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Institute for Nanobiotechnology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Nanomedicine. 2018 Feb;14(2):237-246. doi: 10.1016/j.nano.2017.10.013. Epub 2017 Nov 7.
Therapeutic cancer vaccines require adjuvants leading to robust type I interferon and proinflammatory cytokine responses in the tumor microenvironment to induce an anti-tumor response. Cyclic dinucleotides (CDNs), a potent Stimulator of Interferon Receptor (STING) agonist, are currently in phase I trials. However, their efficacy may be limited to micromolar concentrations due to the cytosolic residence of STING in the ER membrane. Here we utilized biodegradable, poly(beta-amino ester) (PBAE) nanoparticles to deliver CDNs to the cytosol leading to robust immune response at >100-fold lower extracellular CDN concentrations in vitro. The leading CDN PBAE nanoparticle formulation induced a log-fold improvement in potency in treating established B16 melanoma tumors in vivo when combined with PD-1 blocking antibody in comparison to free CDN without nanoparticles. This nanoparticle-mediated cytosolic delivery method for STING agonists synergizes with checkpoint inhibitors and has strong potential for enhanced cancer immunotherapy.
治疗性癌症疫苗需要佐剂，在肿瘤微环境中引发强烈的 I 型干扰素和促炎细胞因子反应，从而诱导抗肿瘤反应。环二核苷酸 (CDN) 是一种有效的干扰素受体 (STING) 激动剂，目前正在进行 I 期临床试验。然而，由于 STING 在 ER 膜中的胞质驻留，其功效可能限于微摩尔浓度。在这里，我们利用可生物降解的聚（β-氨基酯）（PBAE）纳米颗粒将 CDN 递送至细胞质，从而导致在体外以 >100 倍低的细胞外 CDN 浓度下产生强烈的免疫反应。与没有纳米颗粒的游离 CDN 相比，当与 PD-1 阻断抗体联合使用时，领先的 CDN PBAE 纳米颗粒制剂在治疗已建立的 B16 黑色素瘤肿瘤方面的效力提高了一个对数级。这种用于 STING 激动剂的纳米颗粒介导的细胞质递送方法与检查点抑制剂协同作用，具有增强癌症免疫治疗的强大潜力。
