State Key Laboratory of Drug Research & Center of Pharmaceutics , Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203 , China.
School of Life Sciences , Jilin University , Changchun 130012 , China.
Nano Lett. 2019 Aug 14;19(8):5266-5276. doi: 10.1021/acs.nanolett.9b01717. Epub 2019 Aug 5.
The long progression-free survival (PFS) of patients with inoperable hepatocellular carcinoma (HCC) tumors is an unmet clinical need. Imaging-guided in situ ablation and vaccination with nanoplatforms could be a promising way to achieve durable disease control and long PFS. In the present work, we show that a biomimetic nanoplatform, namely, synthetic high-density lipoprotein (sHDL), can transport photothermal agent DiR and other drugs preferentially into the cytosol of HCC cells, enabling imaging-guided combination therapy for HCC in vivo. With a single injection, the sHDLs reduced the tumor burden, triggered immunogenic cell death (ICD), promoted dendritic cell (DC) maturation, and induced CD8 T cell responses, which together sensitized the tumors to PD-1 blockade. Tumor remission and immune protection were achieved using sHDL loaded with DiR and a stimulator of interferon genes agonist vadimezan, in conjunction with a PD-1 blockade. The replacement of vadimezan with the chemotherapeutic mertansine potentiated ICD of HCC cells, but the drug interfered with DC maturation and subsequent CD8 T cell priming, resulting in unsatisfactory disease control. Our work provides a generalizable nanoplatform for the combined photothermal ablation and immunotherapy of HCC and highlights the importance of cancer-cell-specific ICD induction and simultaneous DC activation during in situ vaccination.
不可切除肝细胞癌 (HCC) 患者的无进展生存期 (PFS) 较长是临床未满足的需求。影像引导的原位消融和纳米平台疫苗接种可能是实现持久疾病控制和长 PFS 的有前途的方法。在本工作中，我们表明仿生纳米平台，即合成高密度脂蛋白 (sHDL)，可以优先将光热剂 DiR 和其他药物运输到 HCC 细胞的细胞质中，从而能够在体内进行影像引导的 HCC 联合治疗。通过单次注射，sHDLs 减少了肿瘤负担，触发了免疫原性细胞死亡 (ICD)，促进了树突状细胞 (DC) 的成熟，并诱导了 CD8 T 细胞反应，这些共同使肿瘤对 PD-1 阻断敏感。sHDL 负载 DiR 和干扰素基因激动剂 vadimezan 联合 PD-1 阻断可实现肿瘤缓解和免疫保护。用化疗药物 mertansine 替代 vadimezan 增强了 HCC 细胞的 ICD，但该药物干扰了 DC 的成熟和随后的 CD8 T 细胞启动，导致疾病控制不理想。我们的工作为 HCC 的联合光热消融和免疫治疗提供了一种可推广的纳米平台，并强调了在原位疫苗接种过程中诱导癌细胞特异性 ICD 和同时激活 DC 的重要性。
