Anna K. Renfrew

Drug delivery of lipophilic pyrenyl derivatives by encapsulation in a water soluble metalla-cage

The self-assembly of 2,4,6-tris(pyridin-4-yl)-1,3,5-triazine (tpt) triangular panels with p-cymene (p-Pr(i)C(6)H(4)Me) ruthenium building blocks and 2,5-dioxydo-1,4-benzoquinonato (dobq) bridges, in the presence of a functionalised pyrenyl derivative (pyrene-R), affords the triangular prismatic host-guest compounds [(pyrene-R) [symbol: see text] Ru(6)(p-Pr(i)C(6)H(4)Me)(6)(tpt)(2)(dobq)(3)](6+) ([(pyrene-R) [symbol: see text] 1](6+)). The inclusion of eight mono-substituted pyrenyl derivatives including biologically relevant structures (a = 1-pyrenebutyric acid, b = 1-pyrenebutanol, c = 1-pyrenemethylamine, d = 1-pyrenemethylbutanoate, e = 1-(4,6-dichloro-1,3,5-triazin-2-yl)pyrene, f = N-hexadecylpyrene-1-sulfonamide, g = pyrenyl ethacrynic amide and h = 2-(pyren-1-ylmethylcarbamoyl) phenyl acetate), and a di-substituted pyrenyl derivative (i = 1,8-bis(3-methyl-butyn-1-yl-3-ol)pyrene), has been accomplished. The carceplex nature of these systems with the pyrenyl moiety being firmly encapsulated in the hydrophobic cavity of the cage with the functional groups pointing outwards was confirmed by NMR ((1)H, 2D, DOSY) spectroscopy and electrospray ionization mass spectrometry (ESI-MS). The cytotoxicities of these water-soluble compounds have been established using human ovarian A2780 cancer cells. All the host-guest systems are more cytotoxic than the empty cage itself [1][CF(3)SO(3)](6) (IC(50) = 23 microM), the most active carceplex [f [symbol: see text] 1][CF(3)SO(3)](6) is an order of magnitude more cytotoxic.

Discovery, structure, and anticancer activity of an iridium complex of diselenobenzoquinone.

Caught in the act: The first stable η4-diseleno-p-benzoquinone complex, [Cp*lr(η4-C6H4Se2)], has been isolated. The X-ray structure confirms the coordination of the elusive diselenobenzoquinone intermediate. The anticancer activity of this complex was compared to related oxygen and sulfur analogs; only the diseleno complex was cytotoxic, having a comparable activity to cisplatin.

Delivery and release of curcumin by a hypoxia-activated cobalt chaperone: a XANES and FLIM study

We present a bioreductively activated cobalt(III) carrier system for the delivery of curcumin with enhanced drug stability, tumour penetration and efficacy in hypoxic tumour regions. Curcumin is a natural product with potent anticancer activity but low bioavailability and serum stability. With the aim of overcoming these limitations, we prepared a cobalt(III) prodrug of curcumin and compared the stability, cytotoxicity and cellular uptake with those of the free drug. Using a combination of fluorescence lifetime imaging and X-ray absorption spectroscopy, we demonstrated that curcumin is released from the cobalt carrier complex in tumour cells, with strong evidence to suggest that the process occurs via reduction of the cobalt centre. Furthermore, fluorescence lifetime imaging in solid tumour models showed that the cobalt complex delivered curcumin uniformly throughout the tumour model, while free curcumin only accumulated on the outer edges. For comparison, we also investigated the isoelectronic ruthenium(II) complex and found its properties and biological activity to be very different to those of the cobalt analogue.

Cobalt(III) Chaperone Complexes of Curcumin: Photoreduction, Cellular Accumulation and Light-Selective Toxicity towards Tumour Cells

Light-activated prodrugs offer the potential for highly selective tumour targeting. However, the application of many photoactivated chemotherapeutics is limited by a requirement for oxygen, or for short activation wavelengths that can damage surrounding tissue. Herein, we present a series of cobalt(III)-curcumin prodrugs that can be activated by visible light under both oxygenated and hypoxic conditions. Furthermore, the photoproduct can be controlled by the activation wavelength: green light yields free curcumin, whereas blue light induces photolysis of curcumin to a phototoxic product. Confocal fluorescence microscopy and phototocytotoxicity studies in DLD-1 and MCF-7 tumour cells demonstrated that the cobalt(III) prodrugs are nontoxic in the dark but accumulate in significant concentrations in the cell membrane. When cells were treated with light for 15  min, the cytotoxicity of the cobalt complexes increased by up to 20-fold, whereas free curcumin exhibited only a two-fold increase in cytotoxicity. The nature of the ancillary ligand and cobalt reduction potential were found to strongly influence the stability and biological activity of the series.

Dual targeting of hypoxic and acidic tumor environments with a cobalt(III) chaperone complex.

The rational design of prodrugs for selective accumulation and activation in tumor microenvironments is one of the most promising strategies for minimizing the toxicity of anticancer drugs. Manipulation of the charge of the prodrug represents a potential mechanism to selectively deliver the prodrug to the acidic tumor microenvironment. Here we present delivery of a fluorescent coumarin using a cobalt(III) chaperone to target hypoxic regions, and charged ligands for pH selectivity. Protonation or deprotonation of the complexes over a physiologically relevant pH range resulted in pH dependent accumulation of the fluorophore in colon cancer cells. Furthermore, in a spheroid solid tumor model, the anionic complexes exhibited preferential release of the fluorophore in the acidic/hypoxic region. By fine-tuning the physicochemical properties of the cobalt-chaperone moiety, we have demonstrated selective drug release in the acidic and hypoxic tumor microenvironment.

Use of Perfluorinated Phosphines to Provide Thermomorphic Anticancer Complexes for Heat-Based Tumor Targeting

A series of compounds of general formula [Ru(eta(6)-arene)(pta)(PR(3))Cl]BF(4) (arene = p-cymene or 4-phenyl-2-butanol; pta = 1,3,5-triaza-7-phosphatricyclo[3.3.1.1]decane, PR(3) = PPh(2)(p-C(6)H(4)C(2)H(4)C(8)F(17)), PPh(p-C(6)H(4)C(2)H(4)C(8)F(17))(2), P(p-C(6)H(4)C(2)H(4)C(6)F(13))(3), PPh(3) or P(p-C(6)H(4)F)(3)) have been prepared and characterized by spectroscopic methods. The structure of [Ru(eta(6)-p-cymene)(pta)Cl(P(p-C(6)H(4)F)(3))]BF(4) has also been established in the solid state by X-ray crystallography. The cytotoxicities of the compounds were determined in the A2780 and A2780 cisplatin-resistant cell lines revealing that the fluorinated phosphines significantly increase antiproliferative activity relative to their bis-chloride precursors. Two of the complexes were found to be thermoresponsive, that is, showing poor water solubility at 37 degrees C and good solubility at 42 degrees C, the temperature of a heated tumor, providing a method of tumor targeting. Incubation at 42 degrees C for 2 h resulted in improved cytotoxicities for two of the complexes.

Reversible magnetogenic cobalt complexes

Cobalt complexes have been extensively used for their catalytic and solid-state magnetic properties, but the solution-state magnetic properties have not yet been widely exploited. Two versatile cobalt ligand scaffolds were investigated for their magnetic properties, which both demonstrated a diamagnetic to paramagnetic transition upon reduction. Notably, one of these complexes, cobalt tris(2-pyridylmethyl)amine (Co-TPA), was capable of cycling between a stable Co(II) species that could induce longitudinal and transverse relaxation of surrounding water protons, and a stable diamagnetic Co(III) species, exhibiting negligible relaxivity effects. Therefore, we propose Co-TPA as a dynamic redox responsive contrast agent for the magnetic resonance imaging (MRI) of hypoxia.

Hypoxia-Responsive Cobalt Complexes in Tumor Spheroids: Laser Ablation Inductively Coupled Plasma Mass Spectrometry and Magnetic Resonance Imaging Studies

Dense tumors are resistant to conventional chemotherapies due to the unique tumor microenvironment characterized by hypoxic regions that promote cellular dormancy. Bioreductive drugs that are activated in response to this hypoxic environment are an attractive strategy for therapy with anticipated lower harmful side effects in normoxic healthy tissue. Cobalt bioreductive pro-drugs that selectively release toxic payloads upon reduction in hypoxic cells have shown great promise as anticancer agents. However, the bioreductive response in the tumor microenvironment must be better understood, as current techniques for monitoring bioreduction to Co(II) such as X-ray absorption near-edge structure and extended X-ray absorption fine structure provide limited information on speciation and require synchrotron radiation sources. Here, we present magnetic resonance imaging (MRI) as an accessible and powerful technique to monitor bioreduction by treating the cobalt complex as an MRI contrast agent and monitoring the change in water signal induced by reduction from diamagnetic Co(III) to paramagnetic Co(II). Cobalt pro-drugs built upon the tris(2-pyridylmethyl)amine ligand scaffold with varying charge were investigated for distribution and activity in a 3D tumor spheroid model by laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) and MRI. In addition, paramagnetic 1H NMR spectroscopy of spheroids enabled determination of the speciation of activated Co(II)TPAx complexes. This study demonstrates the utility of MRI and associated spectroscopy techniques for understanding bioreductive cobalt pro-drugs in the tumor microenvironment and has broader implications for monitoring paramagnetic metal-based therapies.

CCDC 1576530: Experimental Crystal Structure Determination

Related Article: Bradley P. Green, Anna K. Renfrew, Alexandra Glenister, Peter Turner, Trevor W. Hambley|2017|Dalton Trans.|46|15897|doi:10.1039/C7DT03645K