From metallodrug design to halochromic nanocarrier delivery: revitalizing the anticancer efficacy and biocompatibility of cyclometalated Ru(ii) complex

Abstract

The clinical success of metal-based anticancer agents can be achieved by developing not only an efficient metallodrug but also a suitable drug delivery system (DDS). Although spatiotemporal delivery, enhancing the efficacy, and alleviating toxicity are achievable, modifying the mechanism of action of metallodrugs using a nano DDS remains scarce. With all this in mind, a series of cyclometalated ruthenium(II) half-sandwich complexes of the type [(η⁶-p-cymene)Ru(L)Cl] Ru(1)–Ru(4), where L is 2-phenylquinoline (L1), 2-(thiophen-2-yl)quinoline (L2), 4-methyl-2-phenylquinoline (L3), or 2,4-diphenylquinoline (L4), have been isolated and characterized by analytical and spectroscopic methods. Ru(1) and Ru(2) have been structurally characterized, and their coordination geometries around the ruthenium(II) are described as pseudo-octahedral geometry. Only the Ru(1) complex, which exhibited substantial cytotoxicity in non-cancerous cells and low cytotoxicity in breast cancer cells, is encapsulated into a hybrid nanosystem comprising phospholipid and polydiacetylene. The Ru(1)-entrapped nanoassembly (PDL-Ru(1)) is found to show pH-induced emission and higher release of the complex in a simulated tumor environment than in a physiological environment. Even though such a halochromic character failed to benefit cell imaging, the nanocarrier-mediated delivery has been proven to improve the cytotoxicity of Ru(1) in breast cancer cells, modulate the mode of cell death, and reduce toxicity in normal cells. Zebrafish embryo toxicity studies revealed that polydiacetylene-lipid nanoassembly could be useful for in vivo biocompatibility applications of ruthenodrug candidates.