College of Marine Life Science, Ocean University of China, Qingdao 266003, PR China.
College of Marine Life Science, Ocean University of China, Qingdao 266003, PR China; Qingdao National Laboratory for Marine Science and Technology, Qingdao 266000, PR China.
J Control Release. 2024 Jun;370:453-467. doi: 10.1016/j.jconrel.2024.04.048. Epub 2024 May 6.
Negative immunoregulatory signal (PD-L1, CXCR4, et al.) and weak immunogenicity elicited immune system failing to detect and destroy cancerous cells. CXCR4 blockade promoted T cell tumor infiltration and increased tumor sensitivity to anti-PD-L1 therapy. Here, pH-responsive reassembled nanomaterials were constructed with anti-PD-L1 peptide and CXCR4 antagonists grafting (APAB), synergized with photothermal therapy for melanoma and breast tumor interference. The self-assembled APAB nanoparticles accumulated in the tumor and rapidly transformed into nanofibers in response to the acidic tumor microenvironment, leading to the exposure of grafted therapeutic agents. APAB enabling to reassemble around tumor cells and remained stable for over 96 h due to the aggregation induced retention (AIR) effect, led to long-term efficiently combined PD-L1 and CXCR4 blockade. Photothermal efficiency (ICG) induced immunogenic cell death (ICD) of tumor cells so as to effectively improve the immunogenicity. The combined therapy (ICG@APAB) could effectively inhibit the growth of primary tumor (∼83.52%) and distant tumor (∼76.24%) in melanoma-bearing mice, and significantly (p < 0.05) prolong the survival time over 42 days. The inhibition assay on tumor metastasis in 4 T1 model mice exhibited ICG@APAB almostly suppressed the occurrence of lung metastases and the expression levels of CD31, MMP-9 and VEGF in tumor decreased by 82.26%, 90.45% and 41.54%, respectively. The in vivo reassembly strategy will offer novel perspectives benefical future immunotherapies and push development of combined therapeutics into clinical settings.
负免疫调节信号（PD-L1、CXCR4 等）和较弱的免疫原性导致免疫系统无法检测和破坏癌细胞。CXCR4 阻断促进了 T 细胞肿瘤浸润，并增加了肿瘤对抗 PD-L1 治疗的敏感性。在这里，构建了具有抗 PD-L1 肽和 CXCR4 拮抗剂接枝（APAB）的 pH 响应性重组纳米材料，与光热疗法协同作用，干扰黑色素瘤和乳腺癌肿瘤。自组装的 APAB 纳米颗粒在肿瘤中积累，并在酸性肿瘤微环境中迅速转化为纳米纤维，导致接枝治疗剂暴露。APAB 能够在肿瘤细胞周围重新组装，并由于聚集诱导保留（AIR）效应而保持稳定超过 96 小时，导致长期高效联合 PD-L1 和 CXCR4 阻断。光热效率（ICG）诱导肿瘤细胞免疫原性细胞死亡（ICD），从而有效提高免疫原性。联合治疗（ICG@APAB）可有效抑制荷瘤小鼠原发性肿瘤（∼83.52%）和远处肿瘤（∼76.24%）的生长，并显著（p < 0.05）延长 42 天以上的存活时间。在 4T1 模型小鼠的肿瘤转移抑制试验中，ICG@APAB 几乎完全抑制了肺转移的发生，肿瘤中 CD31、MMP-9 和 VEGF 的表达水平分别降低了 82.26%、90.45%和 41.54%。体内重组策略将为未来的免疫疗法提供新的视角，并推动联合治疗进入临床应用。
