Enhanced passive diffusion is usually considered to be the primary cause of the enhanced cellular uptake of cyclometalated drugs because cyclometalation lowers the charge of a metal complex and increases its lipophilicity. We will discuss our alternative observations on monocationic cyclometalated metal complexes that self-assemble into supramolecular nanostructures, while their polypyridyl bicationic analogues remain isolated in solution. These nanostructures formed via metallophilic M...M interaction and π−π stacking, and interestingly they were stabilized in cell medium by serum proteins, in the absence of which the nanorods precipitated. In cell cultures, these protein-stabilized self-assembled nanorods were responsible for the improved cellular uptake of the cyclometalated compounds, which took place via endocytosis, i.e., an active uptake pathway, rather than passive diffusion. In addition to triggering self-assembly, cyclometalation also led to dramatically enhanced photomedicinal properties under blue light irradiation: either phototoxicity with M=Pd(II),<sup>1</sup> or phosphorescence with M=Pt(II).<sup>2</sup> These combined self-assembly and photochemical properties were observed in multicellular tumor spheroids and in a mice tumor xenograft, demonstrating that protein-stabilized nanoaggregation of cyclometalated drugs also allows efficient cellular uptake in 3D tumor models. Overall, serum proteins appear to be a major element in drug design because they strongly influence the size and bioavailability of supramolecular drug aggregates and hence their efficacy in vitro and in vivo.

Self-assembling light-activated drugs for cancer imaging and therapy

ACS Fall 2021

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