Ferrocifens labelled with an infrared rhenium tricarbonyl tag: synthesis, antiproliferative activity, quantification and nano IR mapping in cancer cells

Abstract

Antiproliferative activities of several members of the ferrocifen family, both in vitro and in vivo, are well documented although their precise location in cancer cells has not yet been elucidated. However, two different infrared imaging techniques have been used to map the non-cytotoxic cyrhetrenyl analogue of ferrociphenol in a single cell. This observation prompted us to tag two ferrocifens with a cyrhetrenyl unit [CpRe(CO)3; Cp = η5-cyclopentadienyl] by grafting it, via an ester bond, either to one of the phenols (4, 5) or to the hydroxypropyl chain (6). Complexes 4-6 retained a high cytotoxicity on breast cancer cells (MDA-MB-231) with IC50 values in the range 0.32-2.5 μM. Transmission IR spectroscopy was used to quantify the amount of cyrhetrenyl tag present in cells incubated with 5 or 6. The results show that after a 1-hour incubation of cells at 37 °C, complexes 5 and 6 are mainly present within cells while only a limited percentage, quantified by ICP-OES, remained in the incubation medium. AFM-IR spectroscopy, a technique coupling infrared irradiation with near-field AFM detection, was used to map the cyrhetrenyl unit in a single MDA-MB-231 cell, incubated at 37 °C for 1 hour with 10 μM of 6. The results show that signal distribution of the characteristic band of the Re(CO)3 entity at 1950 cm-1 matched those of amide and phosphate, thus indicating a location of the complex mainly in the cell nucleus.

Intracellular Localization of an Osmocenyl‐Tamoxifen Derivative in Breast Cancer Cells Revealed by Synchrotron Radiation X‐ray Fluorescence Nanoimaging

“…Previous multimodal optical imaging studies of arhenium-(I) carbonyl derivative of mestranol in MDB-MB-231 cells showed preferential accumulation in another highly membranous organelle namely,t he golgi apparatus, [15] while recently,amixed ferrocenyl/ rhenium(I) carbonyl tamoxifen derivative was located, by nano-IR imaging,m ainly in the nucleus of MDA-MB-231 cells. [16] This contrasts dramatically with the cellular distribution of another anticancer cationic half-sandwich Os(II) complex, which was found mainly located in the mitochondria by the same nanoimaging technique and cellular fractionation coupled to inductively coupled plasma-mass spectrometry (ICP-MS) analysis. [11] Chemically fixed cells were further analyzed by 3D X-ray fluorescence nanoimaging.W hile 2D-XRF imaging informs on the projected elemental distribution across the cell thickness,3 DX RF provides depth information and discriminates between intracellular,s urface and extracellular locations of elements (both endogenous and exogenous).…”

Intracellular Localization of an Osmocenyl‐Tamoxifen Derivative in Breast Cancer Cells Revealed by Synchrotron Radiation X‐ray Fluorescence Nanoimaging

“…Previous multimodal optical imaging studies of a rhenium(I) carbonyl derivative of mestranol in MDB‐MB‐231 cells showed preferential accumulation in another highly membranous organelle namely, the golgi apparatus, while recently, a mixed ferrocenyl/ rhenium(I) carbonyl tamoxifen derivative was located, by nano‐IR imaging, mainly in the nucleus of MDA‐MB‐231 cells . This contrasts dramatically with the cellular distribution of another anticancer cationic half‐sandwich Os(II) complex, which was found mainly located in the mitochondria by the same nanoimaging technique and cellular fractionation coupled to inductively coupled plasma‐mass spectrometry (ICP‐MS) analysis …”

Importance of Combining Advanced Particle Size Analysis Techniques To Characterize Cell-Penetrating Peptide–Ferrocifen Self-Assemblies

“…These CPPs can be used to transport various hydrophobic anticancer drugs such as promising organometallic molecules: ferrocifen which combine hydroxytamoxifen and ferrocene together 10,11 . They present major properties as stability in non-oxidative environment, reversible oxidation-reduction (redox) potential, and impressive antiproliferative effects on various cancer cells [12][13][14] . The action mechanism of ferrocifens can be related to the oxidation state of iron in the ferrocene moiety.…”