pH-Responsive, Self-Assembled Ruthenium Nanodrug: Dual Impact on Lysosomes and DNA for Synergistic Chemotherapy and Immunogenic Cell Death

Yu Lu; Di Zhu; Bo Hu; Rong Chen; Xin Wang; Xiaoxue Xu; Wenjing Wang; Hao Wu; Yuji Wang

doi:10.1002/smll.202310636

pH-Responsive, Self-Assembled Ruthenium Nanodrug: Dual Impact on Lysosomes and DNA for Synergistic Chemotherapy and Immunogenic Cell Death

Small. 2024 Feb 27:e2310636. doi: 10.1002/smll.202310636. Online ahead of print.

Authors

Yu Lu^{1

2}, Di Zhu^{1

2}, Bo Hu^{1

2}, Rong Chen^{1

2}, Xin Wang^{1

2}, Xiaoxue Xu³, Wenjing Wang⁴, Hao Wu⁵, Yuji Wang^{1

2}

Affiliations

¹ Department of Medicinal Chemistry, College of Pharmaceutical Sciences of Capital Medical University, Beijing, 100069, P. R. China.
² 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.
³ Department of Core Facility Center, Capital Medical University, Beijing, 100069, P. R. China.
⁴ Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing, 100069, P. R. China.
⁵ Xuanwu Hospital, Capital Medical University, Beijing, 100053, P. R. China.

PMID: 38412413
DOI: 10.1002/smll.202310636

Abstract

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.

Keywords: DNA damage; immunogenic cell death; lysosome; ruthenium complex; self-assembly.

Abstract

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