Luminescent Bimetallic IrIII /AuI Peptide Bioconjugates as Potential Theranostic Agents.

Invited for the cover of this issue are Vanesa Fernández-Moreira, Nils Metzler-Nolte, M. Concepción Gimeno and co-workers at Universidad de Zaragoza and Ruhr-Universität Bochum. The image depicts the reported bimetallic bioconjugates as planes directing the gold fragment towards the target (lysosomes). Read the full text of the article at 10.1002/chem.202002067.

Luminescent Bimetallic IrIII /AuI Peptide Bioconjugates as Potential Theranostic Agents.

Diverse iridium peptide bioconjugates and the corresponding iridium/gold bimetallic complexes have been synthesized starting from a cyclometallated carboxylic acid substituted IrIII complex [Ir(ppy)2 (Phen-5-COO)] by solid phase peptide synthesis (SPPS). The selected peptide sequences were an enkephalin derivative Tyr-Gly-Gly-Phe-Leu together with the propargyl-substituted species Tyr-Gly-Pgl-Phe-Leu to allow gold coordination (Pgl: propyrgyl-glycine, HC≡C-Gly), and a specific short peptide, Ala-Cys-Ala-Phen, containing a cysteine residue. Introduction of the gold center has been achieved via a click reaction with the alkynyl group leading to an organometallic Au-C(triazole) species, or by direct coordination to the sulfur atom of the cysteine. The photophysical properties of these species revealed predominantly an emission originating from the Ir complex, using mixed metal-to-ligand and ligand-to-ligand charge transfer excited states of triplet multiplicity. The formation of the peptide bioconjugates caused a systematic redshift of the emission profiles. Lysosomal accumulation was observed for all the complexes, in contrast to the expected mitochondrial accumulation triggered by the gold complexes. Only the cysteine-containing Ir/Au bioconjugate displayed cytotoxic activity. The absence of activity may be related to the lack of endosomal/lysosomal escape for the cationic peptide conjugates. Interestingly, the different coordination sphere of the gold atom may play a crucial role, as the Au-S(cysteine) bond may be more readily cleaved in a biological environment than the Au-C(triazole) bond, and thus the Au fragment could be released from or trapped in the lysosomes, respectively. This work represents a starting point in the development of bimetallic peptide bioconjugates as theranostics and in the knowledge of factors that contribute to anti-proliferative activity.

Luminescent Re(I)/Au(I) Species As Selective Anticancer Agents for HeLa Cells.

A series of neutral and cationic heterotrimetallic complexes of the type fac-[Re(CO)3(bipy(CC)2-(AuL)2)X]n, where bipy(CC)2 is 4,4'-alkynyl-2,2'-bipyridine; L is either triphenylphosphine (PPh3), [1,3-bis(2,6-diisopropylphenyl)-imidazol-2-ylidene] (IPr), or tert-butyl isocyanide (CNtBu); and X is a chloride (n = 0) or acetonitrile (n = 1), were synthesized and characterized together with their Re(I) precursors, i.e., fac-[Re(CO)3(bipy(CC)2)X]n. X-ray diffraction of complexes 1, 3, and 6 corroborated the expected octahedral and linear distribution of the ligands along the Re(I) and Au(I) centers, respectively. Luminescent studies showed that all the complexes displayed a broad emission band centered between 565 and 680 nm, corresponding to a 3MLCT from the Re(I) to the diimine derivative. The presence of the gold fragment coordinated to the diimine ligand shifted in all cases the emission maxima toward higher energies. Such an emission difference could be potentially used for assessing the precise moment of interaction of the probe with the biological target if the gold fragment is implicated. Antiproliferative studies in cancer cells, A549 (lung cancer) and HeLa (cervix cancer), showed a generalized selectivity toward HeLa cells for those heterotrimetallic species incubated at longer times (72 vs 24 h). ICP-MS spectrometry revealed the greater cell internalization of cationic vs neutral species. Preliminary fluorescence microscopy experiments showed a different behavior of the complexes in HeLa and A549 cell lines. Whereas the complexes in A549 were randomly distributed in the outside of the cell, those incubated with HeLa cells were located close to the cellular membrane, suggesting some type of interaction, and possibly explaining their cellular selectivity when it comes to the antiproliferative activity displayed in the different cell lines.

Trackable Metallodrugs Combining Luminescent Re(I) and Bioactive Au(I) Fragments.

Hetero-bimetallic and -trimetallic complexes were synthesized by the combination of different metallic fragments, a luminescent Re(I) species, and a bioactive Au(I) derivative. A ditopic P,N-donor ligand (L) was used as linker between both metals, affording six new bipyridine (bipy) Re(I)/Au(I) hetero-metallic complexes of the type fac-[Re(bipy)(CO)3(LAuCl)]+ (4-6) and [(fac-[Re(bipy)(CO)3(L)])2Au]3+ (7-9) after a thorough synthetic procedure. Their emission is associated with a triplet metal-to-ligand charge transfer (Re(dπ) → bipy(π*)) transition and red-shifted in polar solvents with lifetimes in the range of nanoseconds and quantum yield values up to 12.5%. Cytotoxicity values in A549 cells of hetero-trimetallic species are almost twice that for the hetero-bimetallic (ca. 37 vs 69 µM, respectively), being the L-Au fragment the source of the antiproliferative activity. Species 7 and 8 showed similar behavior by fluorescence microscopy, with a nonuniform cytoplasmatic distribution, a clear accumulation in single spots at the edge of the inner cell membrane as well as in areas within the nucleus. Preliminary studies suggest the DNA as one of the targets and passive diffusion as the entrance pathway.

Denervación simpática de una extremidad como forma de presentación en cáncer del vértice pulmonar / Sympathetic denervation of an upper limb as a presentation form of an apical lung cancer

We report a 56 years old male patient presenting with a sympathetic denervation of the right upper limb due to an apical lung cancer. Vasomotor paralysis of the limb was objectively documented with a contact termography. The clinical presentation of this patient was unusual, considering that the alteration occurred without sensory or motor changes of the limb or autonomic disturbances of the face. The absence of clinical and neurophysiological involvement of large and small caliber fibres of the brachial plexus and the lack of autonomic dysfunction of the face was explained by a predominant tumoral infiltration of T2 and T4 ventral roots, wich supply autonomic innervation to the upper limbs