Doxorubicin and Anti-PD-L1 Antibody Conjugated Gold Nanoparticles for Colorectal Cancer Photochemotherapy
Doxorubicin and Anti-PD-L1 Antibody Conjugated Gold Nanoparticles for Colorectal Cancer Photochemotherapy
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DOI：
10.1021/acs.molpharmaceut.8b01157
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发表时间：
2019-03-01
影响因子：
4.9
通讯作者：
Yook, Simmyung
中科院分区：
文献类型：
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作者：
Emami, Fakhrossadat;Banstola, Asmita;Yook, Simmyung
结直肠癌（CRC）是全球癌症相关死亡的第三大原因。已知CRC的预后和总生存期与PD-L1的过表达显著相关。由于联合治疗可以显著提高疗效，我们构建了阿霉素（DOX）结合的抗PD-L1靶向金纳米粒子（PD-L1-AuNP-DOX），用于CRC的靶向化学光热治疗。使用酰胺键将DOX和抗PD-L1抗体缀合至硫辛酸聚乙二醇N-羟基琥珀酰亚胺（LA-PEG-NHS）的α末端基团，并且通过使用硫醇-Au共价键将LA-PEG-DOX、LA-PEG-PD-L1和AuNP表面上的短PEG链连接来构建PD-L1-AuNP-DOX。在近红外（NIR）辐射存在下进行PD-L1-AuNP-DOX的理化表征和生物学研究（使用CT-26细胞中的细胞摄取、细胞凋亡和细胞周期测定进行生物学研究）。成功构建了PD-L1-AuNP-DOX（40.0 +/-3.1 nm），并促进了DOX的有效细胞内摄取，如CT-26细胞中显著的凋亡效应（66.0%）所证明的。PD-L1-AuNP-DOX处理加NIR照射通过增加细胞凋亡和细胞周期阻滞显著且协同地抑制CT-26细胞的体外增殖。该研究表明，PD-L1-AuNP-DOX与协同靶向化学光热疗法联合治疗局部CRC具有相当大的潜力。
Colorectal cancer (CRC) is the third leading cause of cancer-related death worldwide. The prognosis and overall survival of CRC are known to be significantly correlated with the overexpression of PD-L1. Since combination therapies can significantly improve therapeutic efficacy, we constructed doxorubicin (DOX) conjugated and anti-PD-L1 targeting gold nanoparticles (PD-L1-AuNP-DOX) for the targeted chemo-photothermal therapy of CRC. DOX and anti-PD-L1 antibody were conjugated to the alpha-terminal end group of lipoic acid polyethylene glycol N-hydroxysuccinimide (LA-PEG-NHS) using an amide linkage, and PD-L1-AuNP-DOX was constructed by linking LA-PEG-DOX, LA-PEG-PD-L1, and a short PEG chain on the surface of AuNP using thiol-Au covalent bonds. Physicochemical characterizations and biological studies of PD-L1-AuNP-DOX were performed in the presence of near-infrared (NIR) irradiation (biologic studies were conducted using cellular uptake, apoptosis, and cell cycle assays in CT-26 cells). PD-L1-AuNP-DOX (40.0 +/- 3.1 nm) was successfully constructed and facilitated the efficient intracellular uptake of DOX as evidenced by pronounced apoptotic effects (66.0%) in CT-26 cells. PD-L1-AuNP-DOX treatment plus NIR irradiation significantly and synergistically suppressed the in vitro proliferation of CT-26 cells by increasing apoptosis and cell cycle arrest. The study demonstrates that PD-L1-AuNP-DOX in combination with synergistic targeted chemo-photothermal therapy has a considerable potential for the treatment of localized CRC.