Cyclic Ruthenium-Peptide Conjugates as Integrin-Targeting Phototherapeutic Prodrugs for the Treatment of Brain Tumors

• Published in: Journal of the American Chemical Society Vol. 145; no. 27; pp. 14963 - 14980
• Main Authors: Zhang, Liyan, Wang, Peiyuan, Zhou, Xue-Quan, Bretin, Ludovic, Zeng, Xiaolong, Husiev, Yurii, Polanco, Ehider A., Zhao, Gangyin, Wijaya, Lukas S., Biver, Tarita, Le Dévédec, Sylvia E., Sun, Wen, Bonnet, Sylvestre
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 12.07.2023
• Subjects: Animals; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; brain; brain neoplasms; Brain Neoplasms - drug therapy; Cell Line, Tumor; Coordination Complexes - chemistry; culture media; diastereomers; glioblastoma; green light; Humans; hydrophilicity; Integrins; irradiation; Mice; nanoparticles; neoplasm cells; Peptides; Peptides, Cyclic; photochemotherapy; phototoxicity; Prodrugs - chemistry; Prodrugs - pharmacology; Prodrugs - therapeutic use; reactive oxygen species; ruthenium; Ruthenium - chemistry; Ruthenium - pharmacology
• ISSN: 0002-7863; 1520-5126; 1520-5126
• DOI: 10.1021/jacs.3c04855

To investigate the potential of tumor-targeting photoactivated chemotherapy, a chiral ruthenium-based anticancer warhead, Λ/Δ-[Ru­(Ph2phen)2(OH2)2]2+, was conjugated to the RGD-containing Ac-MRGDH-NH2 peptide by direct coordination of the M and H residues to the metal. This design afforded two diastereoisomers of a cyclic metallopeptide, Λ-[1]­Cl2 and Δ-[1]­Cl2. In the dark, the ruthenium-chelating peptide had a triple action. First, it prevented other biomolecules from coordinating with the metal center. Second, its hydrophilicity made [1]­Cl2 amphiphilic so that it self-assembled in culture medium into nanoparticles. Third, it acted as a tumor-targeting motif by strongly binding to the integrin (K d = 0.061 μM for the binding of Λ-[1]­Cl2 to αIIbβ3), which resulted in the receptor-mediated uptake of the conjugate in vitro. Phototoxicity studies in two-dimensional (2D) monolayers of A549, U87MG, and PC-3 human cancer cell lines and U87MG three-dimensional (3D) tumor spheroids showed that the two isomers of [1]­Cl2 were strongly phototoxic, with photoindexes up to 17. Mechanistic studies indicated that such phototoxicity was due to a combination of photodynamic therapy (PDT) and photoactivated chemotherapy (PACT) effects, resulting from both reactive oxygen species generation and peptide photosubstitution. Finally, in vivo studies in a subcutaneous U87MG glioblastoma mice model showed that [1]­Cl2 efficiently accumulated in the tumor 12 h after injection, where green light irradiation generated a stronger tumoricidal effect than a nontargeted analogue ruthenium complex [2]­Cl2. Considering the absence of systemic toxicity for the treated mice, these results demonstrate the high potential of light-sensitive integrin-targeted ruthenium-based anticancer compounds for the treatment of brain cancer in vivo.