Department of Pharmacy , Changhai Hospital, Second Military Medical University , Shanghai 200433 , China.
Department of Clinical Pharmacy and Pharmaceutical Management , Fudan University School of Pharmacy , Shanghai 201203 , China.
ACS Appl Mater Interfaces. 2019 Oct 30;11(43):39513-39524. doi: 10.1021/acsami.9b13354. Epub 2019 Oct 18.
Cancer immunotherapy can enhance the antitumor effect of drugs through a combinatorial approach in a synergistic manner. However, the effective targeted delivery of various drugs remains a challenge. We generated a peptide assembling tumor-targeted nanodelivery system based on a breast cancer homing and penetrating peptide for the codelivery of a programmed cell death ligand 1 (PD-L1) small interfering RNA (siRNA) (siPD-L1) and an indoleamine 2,3-dioxygenase inhibitor as a dual blockade of an immune checkpoint. The vector is capable of specifically accumulating in the breast cancer tumor site in a way that allows the siRNA to escape from endosomal vesicles after being endocytosed by tumor cells. The drug within these cells then acts to block tryptophan metabolism. The results showed that locally released siPD-L1 and 1-methyl-dl-tryptophan favor the survival and activation of cytotoxic T lymphocytes, resulting in apoptosis of breast cancer cells. Therefore, this study provides a potential approach for treating breast cancer by blocking immunological checkpoints through the assembly of micelles with functional peptides.
癌症免疫疗法可以通过协同的组合方法增强药物的抗肿瘤效果。然而，各种药物的有效靶向递送仍然是一个挑战。我们基于一种乳腺癌归巢和穿透肽生成了一种肽组装的肿瘤靶向纳米递药系统，用于共递送程序性细胞死亡配体 1（PD-L1）小干扰 RNA（siRNA）（siPD-L1）和吲哚胺 2,3-双加氧酶抑制剂，作为免疫检查点的双重阻断。该载体能够特异性地在乳腺癌肿瘤部位聚集，使得被肿瘤细胞内吞后，siRNA 能够从内体小泡中逃逸。这些细胞内的药物随后作用于阻断色氨酸代谢。结果表明，局部释放的 siPD-L1 和 1-甲基-dl-色氨酸有利于细胞毒性 T 淋巴细胞的存活和激活，导致乳腺癌细胞凋亡。因此，本研究通过组装具有功能肽的胶束来阻断免疫检查点，为治疗乳腺癌提供了一种潜在的方法。
