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

Abstract

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. ; Fax: +61 2 9351 3329; Tel: +61 2 9351 4233 † Electronic supplementary information (ESI) available. See

An Esculetin–Cobalt(III) Archetype for Redox‐Activated Drug Delivery Platforms with Hypoxic Selectivity

“…The spectra in water and PBS buffer (pH 7.4) are similar to that in DMSO, with a small shift in the emission maxima, observed at 468 nm in both water and buffer solutions . A decrease in fluorescence intensity upon coordination has been observed for a number cobalt(III) complexes with different fluorophores and attributed to electron or energy transfer processes …”

“…[28] A decrease in fluorescence intensity upon coordination has been observed for a number cobalt(III) complexes with different fluorophores and attributed to electron or energy transfer processes. [29][30][31] The cyclic voltammogram of complex 1 in MeCN, revealed a pair of waves at -1.09 V and -0.74 V vs. Fc/Fc + , assigned to a metal centered (Co 3+ /Co 2+ ) one-electron reduction and oxidation, respectively ( Figure 2). The large ΔE value (0.35 V) indicates a tendency to irreversibility that hampers the determination of E 1/2 , a parameter typically used to define the reduction potential of redox-activated drug delivery candidates.…”

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

“…A series of cobalt(III) curcumin complexes with different N,N, N , N ‐ tripodal ligands were prepared (Figure 1). All complexes are analogues of the tris(2‐pyridylmethyl)amine (tpa) complex 1 , which we have previously shown to be an effective chaperone for curcumin 20. Complexes 2 and 3 contain modified tpa ligands with one or two carboxylic acid groups, appended in the 3‐position to avoid coordination.…”

“…The levels of fluorescence for cells treated with 1 – 4 were quantified with respect to those of cells treated with free curcumin, using a standard curve of curcumin cellular fluorescence versus concentration (Figure 4 a,b, Figure S7 in the Supporting Information). Though the intact complexes are weakly fluorescent, we have previously established using fluorescence lifetime imaging (FLIM) that the fluorescence in cells treated with complex 1 is predominately due to uncomplexed curcumin 20. As 2 – 4 release curcumin in solution under the same conditions as 1 , and more readily in the cases of 2 and 3 , it is likely that the fluorescence observed is also largely due to free curcumin.…”

“…We have recently demonstrated the use of a cobalt(III) chaperone complex, complex 1 , for the delivery and release of the anticancer therapeutic curcumin. 1 accumulates in the hypoxic regions of a spheroid solid tumour model and releases curcumin through reduction to cobalt(II) 20. Knowing that structurally similar cobalt(III) hydroxyketone complexes undergo photoreduction and photosubstitution reactions,21 here we report an investigation into the possibility of using visible light to activate cobalt(III)‐curcumin prodrug complexes.…”