ABSTRACT
The use of a triphenylarsonium vector for tumour cell-targeting leads to a dramatic increase in Gd3+ uptake in human glioblastoma multiforme cells by up to an order of magnitude over the isosteric triarylphosphonium analogue, with significant implications for 'theranostic' applications involving delivery of this important lanthanoid metal ion to tumour cells.
Subject(s)
Antineoplastic Agents/chemistry , Arsenicals/chemistry , Chelating Agents/chemistry , Gadolinium/chemistry , Antineoplastic Agents/metabolism , Arsenicals/metabolism , Cell Line, Tumor , Chelating Agents/metabolism , Chelating Agents/toxicity , Gadolinium/metabolism , Humans , Precision Medicine/methodsABSTRACT
Glial support is critical for normal axon function and can become dysregulated in white matter (WM) disease. In humans, loss-of-function mutations of KCNJ10, which encodes the inward-rectifying potassium channel KIR4.1, causes seizures and progressive neurological decline. We investigated Kir4.1 functions in oligodendrocytes (OLs) during development, adulthood and after WM injury. We observed that Kir4.1 channels localized to perinodal areas and the inner myelin tongue, suggesting roles in juxta-axonal K+ removal. Conditional knockout (cKO) of OL-Kcnj10 resulted in late onset mitochondrial damage and axonal degeneration. This was accompanied by neuronal loss and neuro-axonal dysfunction in adult OL-Kcnj10 cKO mice as shown by delayed visual evoked potentials, inner retinal thinning and progressive motor deficits. Axon pathologies in OL-Kcnj10 cKO were exacerbated after WM injury in the spinal cord. Our findings point towards a critical role of OL-Kir4.1 for long-term maintenance of axonal function and integrity during adulthood and after WM injury.
Subject(s)
Axons/metabolism , Leukoencephalopathies/genetics , Potassium Channels, Inwardly Rectifying/genetics , Seizures/genetics , Animals , Axons/pathology , Humans , Leukoencephalopathies/physiopathology , Mice , Mice, Knockout , Neuroglia/metabolism , Neuroglia/pathology , Neurons/metabolism , Neurons/pathology , Oligodendroglia/metabolism , Oligodendroglia/pathology , Seizures/physiopathology , Spinal Cord/metabolism , Spinal Cord/physiopathologyABSTRACT
The synthesis of a series of bifunctional Gd(III) complexes 1-3 covalently bound to arylphosphonium cations possessing a varying degree of delocalisation at the phosphonium centre is presented. The influence of the degree of delocalisation was investigated with regards to in vitro cytotoxicity, cellular uptake of Gd, tumor-cell selectivity and intracellular localisation of Gd within human glioblastoma (T98G) and human glial (SVG p12) cells. Cellular uptake and selectivity studies for the Gd(III) complexes indicate that a reduced delocalisation at the phosphonium centre can lead to an enhanced Gd uptake into SVG p12 cells which results in a decrease in the overall tumor cell selectivity. Synchrotron X-ray fluorescence (microbeam XRF) imaging has demonstrated for the first time that uniform uptake of Gd(III) complex 2 within a population of T98G cells increased as a function of increasing Gd incubation times. The Gd maps show dispersed spots of high intensity which are consistent with mitochondrial uptake.
Subject(s)
Coordination Complexes/pharmacology , Gadolinium/chemistry , Onium Compounds/pharmacology , Organophosphorus Compounds/pharmacology , Cell Line, Tumor/metabolism , Coordination Complexes/chemistry , Coordination Complexes/metabolism , Coordination Complexes/toxicity , Humans , Mitochondria/metabolism , Molecular Structure , Onium Compounds/chemistry , Onium Compounds/metabolism , Onium Compounds/toxicity , Organophosphorus Compounds/chemistry , Organophosphorus Compounds/metabolism , Organophosphorus Compounds/toxicityABSTRACT
A structure-activity relationship study of a library of novel bifunctional Gd(III) complexes covalently linked to arylphosphonium cations is reported. Such complexes have been designed for potential application in binary cancer therapies such as neutron capture therapy and photon activation therapy. A positive correlation was found between lipophilicity and cytotoxicity of the complexes. Mitochondria uptake was determined by means of inductively coupled plasma mass spectrometry (ICP-MS), and Gd uptake was determined by means of quantification using synchrotron X-ray fluorescence (XRF) imaging. A negative correlation between lipophilicity and tumour selectivity of the Gd(III) complexes was demonstrated. This study highlights the delicate balance required to minimise in vitro cytotoxicity and optimise in vitro tumour selectivity and mitochondrial localisation for this new class of mitochondrially-targeted binary therapy agents. We also report the highest in vitro tumour selectivity for any Gd agent reported to date, with a T/N (tumour/normal cell) ratio of up to 23.5±6.6.
Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Gadolinium/chemistry , Gadolinium/pharmacology , Mitochondria/metabolism , Organophosphorus Compounds/chemistry , Organophosphorus Compounds/pharmacology , Antineoplastic Agents/pharmacokinetics , Cell Line, Tumor , Gadolinium/pharmacokinetics , Humans , Mass Spectrometry , Mitochondria/pathology , Neoplasms/drug therapy , Neoplasms/metabolism , Neoplasms/pathology , Organophosphorus Compounds/pharmacokinetics , Spectrometry, X-Ray EmissionABSTRACT
Relative to other polycyclic frameworks (1-3), a carborane cage (4 and Cs·5) exerts a significant biological effect as an inhibitor of the purinergic P2X7 receptor (P2X7R) which allows one to target depression in vivo and thus demonstrate, for the first time, that a carborane has the capacity to modify CNS activity.
Subject(s)
Antidepressive Agents/therapeutic use , Central Nervous System/drug effects , Depression/drug therapy , Polycyclic Compounds/therapeutic use , Purinergic P2X Receptor Antagonists/therapeutic use , Receptors, Purinergic P2X7/metabolism , Animals , Antidepressive Agents/chemistry , Central Nervous System/metabolism , Humans , Polycyclic Compounds/chemistryABSTRACT
The first bifunctional Gd(III) complexes covalently bound to arylphosphonium cations and the first tumour-cell selective mitochondrial agents designed for potential application in binary cancer therapies are reported. The highest in vitro cellular uptake for any Gd complex reported to date is described, with levels exceeding 10(10) Gd atoms per tumour cell.
Subject(s)
Antineoplastic Agents/pharmacology , Gadolinium/pharmacology , Mitochondria/drug effects , Neoplasms/drug therapy , Organometallic Compounds/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/metabolism , Cell Line, Tumor , Dose-Response Relationship, Drug , Drug Design , Drug Screening Assays, Antitumor , Gadolinium/chemistry , Gadolinium/metabolism , Humans , Mitochondria/chemistry , Mitochondria/metabolism , Molecular Structure , Neoplasms/metabolism , Neoplasms/pathology , Organometallic Compounds/chemistry , Organometallic Compounds/metabolism , Structure-Activity RelationshipABSTRACT
The preparation of boronated triaryl and tetraaryl phosphonium salts of the type [PPh(3)CH(2)R]Br [R is 4-boronophenyl (1), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-yl)phenyl (2), 3-boronophenyl (3), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-yl)phenyl (4), 2-boronophenyl (5), 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-yl)phenyl (6), and closo-1,2-carboran-1-yl (7)] is described. These compounds were prepared by the reaction of triphenylphosphine with benzylic bromides or 1-bromomethyl-closo-1,2-carborane in acetonitrile solution at 85 °C. The zwitterionic nido-7,8-carborane derivative PPh(3)CH(2)C(2)B(9)H(11) (8) was prepared by treatment of 7 with cesium fluoride in refluxing ethanol. All compounds were fully characterized by multinuclear ((1)H, (11)B, (13)C, and (31)P) 1D- and 2D-NMR spectroscopy, electrospray ionization mass spectrometry, and elemental analysis, and single-crystal X-ray structures were determined for compounds 1, 3, 7, and 8. The cytotoxicities and boron uptake of selected derivatives were investigated in vitro using human glioblastoma (T98G) and canine kidney tubule (MDCK II) cells. The zwitterionic species 8 was found to be the least cytotoxic agent while also delivering the greatest amount of boron to the T98G cells, peaking at 9.15 ± 2.65 µg B/mg protein.
