The Self-Assembly of a Cyclometalated Palladium Photosensitizer into Protein-Stabilized Nanorods Triggers Drug Uptake In Vitro and In Vivo.
J Am Chem Soc
; 142(23): 10383-10399, 2020 06 10.
Article
en En
| MEDLINE
| ID: mdl-32378894
ABSTRACT
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.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Compuestos Organometálicos
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Paladio
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Proteínas Sanguíneas
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Fármacos Fotosensibilizantes
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Nanotubos
Límite:
Humans
Idioma:
En
Revista:
J Am Chem Soc
Año:
2020
Tipo del documento:
Article
País de afiliación:
Países Bajos