Selective aggregation of a platinum-gadolinium complex within a tumor-cell nucleus.

Gadolinium(III) complexes are widely used in magnetic resonance imaging (MRI) as water relaxation agents to improve image contrast. Therapeutic gadolinium-containing agents are also known in which the metal complex enhances tumor response to chemotherapeutics such as cisplatin, or, more commonly, acts as a radiosensitizer in the treatment of diseases, such as cancer. Gadoliniummay also play an important role in therapeutic techniques, such as synchrotron stereotactic radiotherapy (SSR), in which the selective delivery of gadolinium to the cell nucleus would significantly enhance the efficacy of the treatment. Indeed, De Stasio and co-workers have demonstrated that motexafinGd, a gadolinium(III) complex of the pentadentate texaphyrin ligand, was accumulated by approximately 90% of glioblastoma cell nuclei in vitro, and its potential exploitation as a GdSSR agent is warranted. In recent years, gadolinium complexes have also been explored as potential agents in an experimental anti-cancer treatment known as gadolinium neutron-capture therapy (GdNCT), which is closely related to the well-established boron neutron-capture therapy (BNCT). GdNCTutilizes the non-radioactive Gd isotope (natural abundance 15.7%) in a highly effective thermal neutron-capture reaction to destroy tumor cells. Gd possesses the largest effective nuclear cross-section of all naturally-occurring elements (2.55 10 barns); this value is approximately 66 times greater than that of the B nucleus. Gd undergoes neutron capture to give the products of internal conversion, accompanying Auger and Coster–Kronig (ACK) electron emission and 7.94 MeVof energy. However, the very limited range of ACK electrons means that the gadolinium complex must be localized in close proximity to critical cellular components, such as the cell nucleus, if the neutron capture reaction is to be exploited effectively. The use of gadolinium(III) complexes as potential GdNCT delivery agents to brain tumors has been described, although the feasibility of using archetypal MRI agents such as Gd-DTPA (DTPA= diethylenetriaminepentaacetic acid) in a clinical context for GdNCT is considered unlikely owing to the limited number of tumor-cell nuclei that have been shown to incorporate gadolinium. Indeed, the number of gadolinium compounds reported to date that have a capacity to aggregate selectively in tumor-cell nuclei, for example, is very limited, and the search for new types of gadolinium(III) complexes with high nuclear affinity has recently been proposed. Herein, we present a new Pt-Gd complex that can effectively target the nuclei of tumor cells by means of a functionalized dtpa ligand linked to two {Pt(terpy)} (terpy= 2,2’:6’,2’’-terpyridine) units that have the capacity to bind DNA in an intercalative manner. Based on prior work with analogous Pt–Ln complexes (Ln=La, Nd, Eu), which were designed to act as luminescent probes for DNA recognition, we reasoned that the related Pt-Gd species 1 would have the capacity to deliver gadolinium to this important biomolecule. In this work, we report the first unequivocal example of gadolinium delivery to a tumor-cell nucleus by a platinum complex. Complex 1was prepared in good yield by a similar manner to that described for the analogous Pt-Ln species (Ln=La, Nd, Eu; Scheme 1). The convenient one-pot synthesis of 1 demonstrates the high affinity of the soft Pt and hard Gd cations for the soft and hard Lewis bases (S and N/O, respectively) that are present in the functionalized DTPA ligand. The purple Pt-Gd complex has excellent solubility and stability in aqueous solution, and no evidence was found for the loss of Pt or Gd ions from 1, even after 24 h of standing in a buffered pH 7.4 solution at room temperature. Preliminary DNA thermal denaturation (DNA melting) experiments involving calf-thymus DNAwere performed on 1 at pH 7.4 (Supporting Information, Figure S1). There exists a significant difference in the melting temperatures between the freeand drug-treated DNA samples (DTm= 4.5 0.5 8C), [*] Dr. E. L. Crossley, Dr. J. B. Aitken, Prof. L. M. Rendina School of Chemistry, The University of Sydney Sydney, NSW 2006 (Australia) Fax: (+61)2-9351-3329 E-mail: [email protected]