Allen Sean D, Liu Xiangsheng, Jiang Jinhong, Liao Yu-Pei, Chang Chong Hyun, Nel Andre E, Meng Huan
Department of Medicine, Division of NanoMedicine, University of California, Los Angeles, CA, USA.
Department of Medicine, Division of NanoMedicine, University of California, Los Angeles, CA, USA; California NanoSystems Institute, University of California, Los Angeles, CA, USA.
Biomaterials. 2021 Feb;269:120635. doi: 10.1016/j.biomaterials.2020.120635. Epub 2020 Dec 28.
Checkpoint blocking antibodies that interfere in the PD-1/PD-L1 axis provide effective cancer immunotherapy for tumors that are immune inflamed or induced to become "hot". It has also been demonstrated that a small molecule inhibitor of the signaling hub kinase GSK3 can interfere in the PD-1/PD-L1 axis in T-cells by suppressing PD-1 expression. This provides an alternative approach to intervening in the PD-1/PD-L1 axis to provide cancer immunotherapy. In this communication, we demonstrate the remote loading of GSK3 inhibitor AZD1080 into the porous interior of mesoporous silica nanoparticles coated with a lipid bilayer (a.k.a. silicasomes). In a MC38 colon cancer model, intravenous injection (IV) of silicasome-encapsulated AZD1080 significantly improved biodistribution and drug delivery to the tumor site. The improved drug delivery was accompanied by cytotoxic MC38 tumor cell killing by perforin-releasing CD8 T-cells, exhibiting reduced PD-1 expression. IV injection of encapsulated AZD1080 also resulted in significant tumor shrinkage in other syngeneic mouse tumor models, including another colorectal tumor (CT26), as well as pancreas (KPC) and lung (LLC) cancer models. Not only was the therapeutic efficacy of encapsulated AZD1080 similar or better than anti-PD-1 antibody, but the treatment was devoid of treatment toxicity. These results provide proof-of-principal demonstration of the feasibility of using encapsulated delivery of a GSK3 inhibitor to provide cancer immunotherapy, with the possibility to be used as a monotherapy or in combination with chemotherapy or other immunomodulatory agents.
干扰PD-1/PD-L1轴的检查点阻断抗体为免疫炎症或诱导变为“热”的肿瘤提供了有效的癌症免疫疗法。也已证明，信号枢纽激酶GSK3的小分子抑制剂可通过抑制PD-1表达来干扰T细胞中的PD-1/PD-L1轴。这为干预PD-1/PD-L1轴以提供癌症免疫疗法提供了一种替代方法。在本通讯中，我们展示了将GSK3抑制剂AZD1080远程装载到涂有脂质双层的介孔二氧化硅纳米颗粒（即硅体）的多孔内部。在MC38结肠癌模型中，静脉注射（IV）包裹有硅体的AZD1080可显著改善生物分布并将药物递送至肿瘤部位。药物递送的改善伴随着通过释放穿孔素的CD8 T细胞对MC38肿瘤细胞的细胞毒性杀伤，表现出PD-1表达降低。静脉注射包裹的AZD1080在其他同基因小鼠肿瘤模型中也导致了显著的肿瘤缩小，包括另一种结肠直肠肿瘤（CT26）以及胰腺（KPC）和肺癌（LLC）模型。包裹的AZD1080的治疗效果不仅与抗PD-1抗体相似或更好，而且该治疗没有治疗毒性。这些结果提供了原理证明，证明了使用包裹递送GSK3抑制剂来提供癌症免疫疗法的可行性，有可能用作单一疗法或与化疗或其他免疫调节剂联合使用。
