The Self-Assembly of a Cyclometalated Palladium Photosensitizer into Protein-Stabilized Nanorods Triggers Drug Uptake In Vitro and In Vivo

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. However, in this work, monocationic cyclometalated
palladium complexes [1]­OAc (N^N^C^N) and [2]­OAc (N^N^N^C) were found
to self-assemble, in aqueous solutions, into soluble supramolecular
nanorods, while their tetrapyridyl bicationic analogue [3]­(OAc)2 (N^N^N^N) dissolved
as
isolated molecules. These nanorods formed via metallophilic Pd···Pd
interaction and π–π stacking and were stabilized
in the 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). In addition to triggering self-assembly,
cyclometalation in [1]­OAc also led to dramatically enhanced
photodynamic properties under blue light irradiation. These combined
penetration and photodynamic properties were observed in multicellular
tumor spheroids and in a mice tumor xenograft, demonstrating that
protein-stabilized nanoaggregation of cyclometalated drugs such as [1]­OAc 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.