The rapid and premature reduction of platinum(IV) complexes in vivo is a significant impediment to these complexes being successfully employed as anticancer prodrugs. This study investigates the influence of the platinum(IV) coordination sphere on the ease of reduction of the platinum center in various biological contexts. In the presence of the biological reductants, ascorbate and cysteine, platinum(IV) complexes with dicarboxylato equatorial ligands were observed to exhibit lower reduction potentials and slower reduction rates than analogous platinum(IV) complexes with dichlorido equatorial ligands. Diaminetetracarboxylatoplatinum(IV) complexes exhibited unusually long half-lives in the presence of excess reductants; however, the complexes exhibited moderate potency in vitro, indicative of rapid reduction within the intracellular environment. By use of XANES spectroscopy, trans-[Pt(OAc)2(ox)(en)] and trans-[PtCl2(OAc)2(en)] were observed to be reduced at a similar rate within DLD-1 cancer cells. This large variability in kinetic inertness of diaminetetracarboxylatoplatinum(IV) complexes in different biological contexts has significant implications for the design of platinum(IV) prodrugs.
Elemental mapping and fluorescence imaging techniques are frequently employed to probe the distribution of platinum-based chemotherapeutics within biological systems. Although useful, these techniques have unique limitations: elemental mapping methods, such as those that use particle beams, typically require rigorous sample preparation that can alter chemical distributions, whilst in situ visible fluorescence studies require fluorescent-tagging of the platinum component and may be confounded by factors such as ligand loss. The present study aimed to establish reliable methods for accurately probing the bio-distribution of platinum compounds within the model tumour micro-environment of the well characterised DLD-1 colorectal cancer cell spheroids. 3D X-ray fluorescence computed micro-tomography (XRF-CT) was performed on intact untreated spheroids to determine the effect of physical sectioning and chemical fixation on elemental distributions. It was revealed for the first time that cisplatin can readily penetrate through DLD-1 spheroids and accumulate in the central hypoxic and necrotic regions of the spheroids. Furthermore, formalin fixing was shown to cause significant changes to the distributions and concentrations of the elements, particularly in the cases of platinum and zinc. This effect was not observed in the cryo-fixed and cryo-sectioned samples. X-ray fluorescence microscopy (XFM) was used to re-examine the fate of platinum in the previously reported fluorescence distribution studies of platinum(ii) complexes tagged with fluorescent anthraquinone moieties. In contrast to the fluorescence distributions, in which fluorescence was observed predominantly around the periphery of the spheroids, the XFM revealed a high level of platinum in the spheroid centre, indicating that ligand exchange occurred within the peripheral cell layers. Both the platinum maps and the fluorescence images exhibit similar diffusion trends, supporting the conclusion that charge on the compound can slow cellular uptake can enhance tumour penetration.
All-trans diammine platinum complexes with four carboxylate donors are stable in the presence of l-ascorbate and blood serum, but are reduced rapidly in whole blood and in cancer cells.
[PtCl2(OAc)2(en)] (red) and [Pt(OAc)2(ox)(en)] (blue) are reduced rapidly in whole blood (right) but the latter was resistant to reduction in human blood serum (left).
A glucose-based
vector for targeting cancer cells conjugated to
a tris(methylpyridyl)amine (tpa) ligand to generate targeted chaperone
and caging complexes for active anticancer agents is described. The
ligand, tpa(CONHPEGglucose)1, inhibits hexokinase, suggesting
that it will be phosphorylated in the cell. A Co(III) complex incorporating
this ligand and coumarin-343 hydroximate (C343ha), [Co(C343ha){tpa(CONHPEGglucose)1}]Cl, is shown to exhibit glucose-dependent cellular accumulation
in DLD-1 colon cancer cells. Cellular accumulation of [Co(C343ha){tpa(CONHPEGglucose)1}]+ is slower than for the glucose null and glucosamine
analogues, and the glucose complex also exhibits a lower ability to
inhibit antiproliferative activity. Distributions of cobalt (X-ray
fluorescence) and C343ha (visible light fluorescence) in DLD-1 cancer
cell spheroids are consistent with uptake of [Co(C343ha){tpa(CONHPEGglucose)1}]+ by rapidly dividing cells, followed by release
and efflux of C343ha and trapping of the Co{tpa(CONHPEGglucose)1} moiety. The Co{tpa(CONHPEGglucose)1} moiety is
shown to have potential for the caged and targeted delivery of highly
toxic anticancer agents.
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