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

• Published in: Photodiagnosis and photodynamic therapy Vol. 41; p. 103412
• Main Authors: ZHOU, Xue-Quan, XIAO, Ming, RAMU, Vadde, HILGENDORF, Jonathan, LI, Xuezhao, PAPADOPOULOU, Panagiota, SIEGLER, Maxime, KROS, Alexander, SUN, Wen, BONNET, Sylvestre
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 01.03.2023
• Subjects: hypoxia; mice models; self-assembly; hypoxia; self-assembly; mice models
• ISSN: 1572-1000; 1873-1597
• DOI: 10.1016/j.pdpdt.2023.103412

Enhanced passive diffusion is usually considered to be the primary cause of the enhanced cellular uptake of cyclometalated metal-based PDT photosensitizers, because cyclometalation lowers the charge of a metal complex and increases its lipophilicity. However, we prepared cyclometalated palladium-based photosensitizers for PDT that self-assemble, in aqueous solutions, into soluble supramolecular nanorods. These nanorods formed via metallophilic Pd···Pd interaction and π−π stacking, and were stabilized in cell medium by serum proteins, in the absence of which they precipitated. In cell cultures, these protein-stabilized self-assembled nanorods were responsible for the improved cellular uptake of the sensitizers, which took place via endocytosis (i.e., an active uptake pathway). In addition to triggering self-assembly, cyclometalation also led to dramatically enhanced photodynamic properties under visible light irradiation, also in hypoxic cancer cells. Such combination of enhanced cellular penetration and type I photodynamic properties were also observed in multicellular tumor spheroids and in mice tumor xenografts, demonstrating that protein-stabilized nanoaggregation of cyclometalated sensitizer allows efficient cellular uptake also in 3-dimensional tumor models. Overall, serum proteins appear to be a major element in the design of PDT photosensitizers, because they strongly influence the size and bioavailability of supramolecular prodrug aggregates, and hence their efficacy in vitro and in vivo.