Department of Medicinal Chemistry, College of Pharmaceutical Sciences of Capital Medical University, Beijing, 100069, P. R. China.
Beijing Area Major Laboratory of Peptide and Small Molecular Drugs, Engineering Research Center of Endogenous Prophylactic of Ministry of Education of China, Beijing Laboratory of Biomedical Materials, Laboratory for Clinical Medicine, Capital Medical University, Beijing, 100069, P. R. China.
Small. 2024 Jun;20(24):e2310636. doi: 10.1002/smll.202310636. Epub 2024 Feb 27.
Several DNA-damaging antitumor agents, including ruthenium complexes, induce immunogenic cell death (ICD). In this study, an arginyl-glycyl-aspartic acid (RGD) peptide-modified carboline ruthenium complex (KS-Ru) is synthesized as a chemotherapeutic nanodrug and an ICD inducer. The RGD peptide, an integrin ligand, provides tumor-specific targeting and promotes self-assembly of the KS-Ru complex. The pH-responsive self-assembly is assessed through transmission and scanning electron microscopy. Additionally, in vitro cytotoxic activity and anti-metastasis ability are evaluated using MTT and Transwell assays, respectively, along with cellular immunofluorescence staining and imaging flow cytometry. The ability of the complex to inhibit primary tumor formation and lung metastasis in vivo is evaluated using Lewis lung cancer and A549 xenograft models. Furthermore, the tumor immune microenvironment is evaluated using single-cell flow mass cytometry. KS-Ru translocates to the nucleus, causing DNA damage and inducing ICD. Within the lysosomes, KS-Ru self-assembled into nanoflowers, leading to lysosomal swelling and apoptosis. Notably, the as-synthesized pH-dependent ruthenium nanomedicine achieves dual functionality-chemotherapy and immunotherapy. Moreover, the pH-responsive self-assembly of KS-Ru enables simultaneous mechanisms in the lysosome and nucleus, thereby lowering the likelihood of drug resistance. This study provides valuable insight for the design of novel ruthenium-based nanoantitumor drugs.
几种 DNA 损伤型抗肿瘤药物，包括钌配合物，可诱导免疫原性细胞死亡（ICD）。在这项研究中，合成了一个精氨酰-甘氨酰-天冬氨酸（RGD）肽修饰的咔啉钌配合物（KS-Ru）作为化疗纳米药物和 ICD 诱导剂。RGD 肽是整合素配体，提供肿瘤特异性靶向，并促进 KS-Ru 配合物的自组装。通过透射电子显微镜和扫描电子显微镜评估 pH 响应自组装。此外，通过 MTT 和 Transwell 测定法分别评估体外细胞毒性活性和抗转移能力，并进行细胞免疫荧光染色和成像流式细胞术。通过 Lewis 肺癌和 A549 异种移植模型评估复合物在体内抑制原发性肿瘤形成和肺转移的能力。此外，通过单细胞流式质谱细胞术评估肿瘤免疫微环境。KS-Ru 易位到细胞核，导致 DNA 损伤并诱导 ICD。在溶酶体中，KS-Ru 自组装成纳米花，导致溶酶体肿胀和凋亡。值得注意的是，所合成的 pH 依赖性钌纳米医学实现了化疗和免疫治疗的双重功能。此外，KS-Ru 的 pH 响应自组装能够在溶酶体和细胞核中同时发挥作用，从而降低耐药性的可能性。这项研究为设计新型基于钌的纳米抗肿瘤药物提供了有价值的见解。
