Chen Ye, Ma He, Wang Wenli, Zhang Min
Department of Pharmacy, Affiliated Qingdao Hiser Hospital of Qingdao University, Qingdao 266034, China.
Institute of Biomedical Materials and Engineering, College of Materials Sciences and Engineering, Qingdao University, Qingdao 266071, China.
Biomater Sci. 2021 Feb 9;9(3):917-929. doi: 10.1039/d0bm01452d.
Although immunotherapy is emerging as a revolutionary strategy for cancer therapy, its clinical effect is severely impaired by adaptive immune evasion and inefficient activation of antitumor immune response. Photodynamic therapy and chemotherapy have been shown to efficiently enhance the therapeutic effect of PD-L1 immunotherapy via different mechanisms. However, the lack of a precise drug delivery system seriously impedes the clinical application of combination therapy. To address these restrictions, a matrix metalloproteinases-2 (MMP2)-activated shrinkable nanosystem was developed to potentiate the antitumor efficacy of anti-PD-L1 antibody (aPDL1) delivered along with a chemo-photodynamic therapy. The nanosystem maintains its structure to accelerate tumor accumulation and shrinks down to a smaller size to facilitate tumor penetration and cellular uptake upon arriving in the tumor microenvironment. The exposure of aPDL1 on the surface of the biodegradable mesoporous silica cores (bMSNs) blocks the PD-1/PD-L1 interaction between tumor cells and T cells. Meanwhile, photosensitizer chlorin e6 (Ce6) and paclitaxel (PTX) loaded bMSNs effectively enter tumor cells and induce chemo-photodynamic therapy. The nanosystem elicits a chemo-photodynamic-induced immune response and improves the therapeutic effect of PD-L1 blockade mediated by aPDL1. Furthermore, the nanosystem displays a sustained prohibitive effect on tumor metastasis to distant sites. Our work presents a promising strategy for enhancing the efficacy of cancer immunotherapy.
尽管免疫疗法正成为一种革命性的癌症治疗策略，但其临床效果因适应性免疫逃逸和抗肿瘤免疫反应激活效率低下而严重受损。光动力疗法和化疗已被证明可通过不同机制有效增强PD-L1免疫疗法的治疗效果。然而，缺乏精确的药物递送系统严重阻碍了联合疗法的临床应用。为了解决这些限制，开发了一种基质金属蛋白酶-2（MMP2）激活的可收缩纳米系统，以增强与化学-光动力疗法一起递送的抗PD-L1抗体（aPDL1）的抗肿瘤功效。该纳米系统保持其结构以加速肿瘤积累，并在到达肿瘤微环境时收缩至更小尺寸，以促进肿瘤渗透和细胞摄取。可生物降解的介孔二氧化硅核（bMSNs）表面上的aPDL1暴露可阻断肿瘤细胞与T细胞之间的PD-1/PD-L1相互作用。同时，负载有光敏剂二氢卟吩e6（Ce6）和紫杉醇（PTX）的bMSNs有效进入肿瘤细胞并诱导化学-光动力疗法。该纳米系统引发化学-光动力诱导的免疫反应，并改善由aPDL1介导的PD-L1阻断的治疗效果。此外，该纳米系统对肿瘤转移至远处部位显示出持续的抑制作用。我们的工作提出了一种增强癌症免疫疗法疗效的有前景的策略。
