In vivo metallophilic self-assembly of a light-activated anticancer drug

• Published in: Nature chemistry Vol. 15; no. 7; pp. 980 - 987
• Main Authors: Zhou, Xue-Quan, Wang, Peiyuan, Ramu, Vadde, Zhang, Liyan, Jiang, Suhua, Li, Xuezhao, Abyar, Selda, Papadopoulou, Panagiota, Shao, Yang, Bretin, Ludovic, Siegler, Maxime A., Buda, Francesco, Kros, Alexander, Fan, Jiangli, Peng, Xiaojun, Sun, Wen, Bonnet, Sylvestre
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.07.2023; NATURE PORTFOLIO; Nature Publishing Group
• Subjects: 631/67/1813/1634; 639/638/263/49; 639/638/439/944; 639/925/352/152; Analytical Chemistry; Animals; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Antitumor agents; Biochemistry; Biocompatibility; Chemistry; Chemistry and Materials Science; Chemistry, Multidisciplinary; Chemistry/Food Science; Chemotherapy; Cytotoxicity; Dosage; Inorganic Chemistry; Irradiation; Light irradiation; Melanoma; Mice; Nanoparticles; Nanoparticles - chemistry; Nanostructure; Nanostructures; Organic Chemistry; Palladium; Physical Chemistry; Physical Sciences; Radiation; Science & Technology; Self-assembly; Skin Neoplasms; Solid tumors; Toxicity; Tumors; NANOPARTICLES; CELLS; POLYPYRIDINE COMPLEX; PHOTODYNAMIC THERAPY; CANCER; DELIVERY
• ISSN: 1755-4330; 1755-4349; 1755-4349
• DOI: 10.1038/s41557-023-01199-w

Self-assembling molecular drugs combine the easy preparation typical of small-molecule chemotherapy and the tumour-targeting properties of drug–nanoparticle conjugates. However, they require a supramolecular interaction that survives the complex environment of a living animal. Here we report that the metallophilic interaction between cyclometalated palladium complexes generates supramolecular nanostructures in living mice that have a long circulation time (over 12 h) and efficient tumour accumulation rate (up to 10.2% of the injected dose per gram) in a skin melanoma tumour model. Green light activation leads to efficient tumour destruction due to the type I photodynamic effect generated by the self-assembled palladium complexes, as demonstrated in vitro by an up to 96-fold cytotoxicity increase upon irradiation. This work demonstrates that metallophilic interactions are well suited to generating stable supramolecular nanotherapeutics in vivo with exceptional tumour-targeting properties. The metallophilic interaction between cyclometalated palladium complexes can facilitate supramolecular nanostructure formation in living mice, providing a phototoxic prodrug with a long circulation time and high tumour-targeting efficiency. Upon green light irradiation, this palladium-based drug destroys solid tumours, leaving non-irradiated organs intact.