In this Minireview, we highlight recent advances in the design of transition metal complexes for photodynamic therapy (PDT) and photoactivated chemotherapy (PACT), and discuss the challenges and ...opportunities for the translation of such agents into clinical use. New designs for light‐activated transition metal complexes offer photoactivatable prodrugs with novel targeted mechanisms of action. Light irradiation can provide spatial and temporal control of drug activation, increasing selectivity and reducing side‐effects. The photophysical and photochemical properties of transition metal complexes can be controlled by the appropriate choice of the metal, its oxidation state, the number and types of ligands, and the coordination geometry.
Light irradiation can provide spatial and temporal control of drug activation, increasing selectivity and reducing side‐effects. This Minireview summarizes new designs for light‐activated transition metal complexes which offer photoactivatable prodrugs with novel targeted mechanisms of action for use in photodynamic therapy (PDT) and photoactivated chemotherapy (PACT).
Gallium-68 (
Ga) is a positron-emitting isotope used for clinical PET imaging of peptide receptor expression.
Ga radiopharmaceuticals used in molecular PET imaging consist of disease-targeting ...biomolecules tethered to chelators that complex
Ga
. Ideally, the chelator will rapidly, quantitatively and stably coordinate
Ga
at room temperature, near neutral pH and low chelator concentration, allowing for simple routine radiopharmaceutical formulation. Identification of chelators that fulfil these requirements will facilitate development of kit-based
Ga radiopharmaceuticals. Herein the reaction of a range of widely used macrocyclic and acyclic chelators with
Ga
is reported. Radiochemical yields have been measured under conditions of varying chelator concentrations, pH (3.5 and 6.5) and temperature (25 and 90 °C). These chelators are: 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA), 1,4,7-triazacyclononane macrocycles substituted with phosphonic (NOTP) and phosphinic (TRAP) groups at the amine, bis(2-hydroxybenzyl)ethylenediaminediacetic acid (HBED), a tris(hydroxypyridinone) containing three 1,6-dimethyl-3-hydroxypyridin-4-one groups (THP) and the hexadentate tris(hydroxamate) siderophore desferrioxamine-B (DFO). Competition studies have also been undertaken to assess relative complexation efficiencies of each chelator for
Ga
under different pH and temperature conditions. Performing radiolabelling reactions at pH 6.5, 25 °C and 5-50 μM chelator concentration resulted in near quantitative radiochemical yields for all chelators, except DOTA. Radiochemical yields either decreased or were not substantially improved when the reactions were undertaken at lower pH or at higher temperature, except in the case of DOTA. THP and DFO were the most effective
Ga
chelators at near-neutral pH and 25 °C, rapidly providing near-quantitative radiochemical yields at very low chelator concentrations. NOTP and HBED were only slightly less effective under these conditions. In competition studies with all other chelators, THP demonstrated highest reactivity for
Ga
complexation under all conditions. These data point to THP possessing ideal properties for rapid, one-step kit-based syntheses of
Ga-biomolecules for molecular PET imaging. LC-MS and
H,
C{
H} and
Ga NMR studies of HBED complexes of Ga
showed that under the analytical conditions employed in this study, multiple HBED-bound Ga complexes exist. X-ray diffraction data indicated that crystals isolated from these solutions contained octahedral Ga(HBED)(H
O), with HBED coordinated in a pentadentate N
O
mode, with only one phenolic group coordinated to Ga
, and the remaining coordination site occupied by a water molecule.
Derivatives of 3,4-hydroxypyridinones have been extensively studied for in vivo Fe
sequestration. Deferiprone, a 1,2-dimethyl-3,4-hydroxypyridinone, is now routinely used for clinical treatment of ...iron overload disease. Hexadentate tris(3,4-hydroxypyridinone) ligands (THP) complex Fe
at very low iron concentrations, and their high affinities for oxophilic trivalent metal ions have led to their development for new applications as bifunctional chelators for the positron emitting radiometal,
Ga
, which is clinically used for molecular imaging in positron emission tomography (PET). THP-peptide bioconjugates rapidly and quantitatively complex
Ga
at ambient temperature, neutral pH and micromolar concentrations of ligand, making them amenable to kit-based radiosynthesis of
Ga PET radiopharmaceuticals.
Ga-labelled THP-peptides accumulate at target tissue in vivo, and are excreted largely via a renal pathway, providing high quality PET images.
KP46 (tris(hydroxyquinolinato)gallium(III)) is an experimental, orally administered anticancer drug. Its absorption, delivery to tumours, and mode of action are poorly understood. We aimed to gain ...insight into these issues using gallium-67 and gallium-68 as radiotracers with SPECT and PET imaging in mice.
GaKP46 and
GaKP46, compared with
Gagallium acetate, were used for log
measurements, in vitro cell uptake studies in A375 melanoma cells, and in vivo imaging in mice bearing A375 tumour xenografts up to 48 h after intravenous (tracer level) and oral (tracer and bulk) administration.
Ga was more efficiently accumulated in A375 cells in vitro when presented as
GaKP46 than as
Gagallium acetate, but the reverse was observed when intravenously administered in vivo. After oral administration of
GaKP46, absorption of
Ga and
Ga from the GI tract and delivery to tumours were poor, with the majority excreted in faeces. By 48 h, low but measurable amounts were accumulated in tumours. The distribution in tissues of absorbed radiogallium and octanol extraction of tissues suggested trafficking as free gallium rather than as KP46. We conclude that KP46 likely acts as a slow releaser of gallium ions which are inefficiently absorbed from the GI tract and trafficked to tissues, including tumour and bone.
Pretargeting is widely explored in immunoPET as a strategy to reduce radiation exposure of non-target organs and allow the use of short-lived radionuclides that would not otherwise be compatible with ...the slow pharmacokinetic profiles of antibodies. Here we investigate a pretargeting strategy based on gallium-68 and the chelator THPMe as a high-affinity pair capable of combining in vivo. After confirming the ability of THPMe to bind 68Ga in vivo at low concentrations, the bifunctional THPMe-NCS was conjugated to a humanised huA33 antibody targeting the A33 glycoprotein. Imaging experiments performed in nude mice bearing A33-positive SW1222 colorectal cancer xenografts compared pretargeting (100 μg of THPMe-NCS-huA33, followed after 24 h by 8–10 MBq of 68Ga3+) with both a directly labelled radioimmunoconjugate (89Zr-DFO-NCS-huA33, 88 μg, 7 MBq) and a 68Ga-only negative control (8–10 MBq of 68Ga3+). Imaging was performed 25 h after antibody administration (1 h after 68Ga3+ administration for negative control). No difference between pretargeting and the negative control was observed, suggesting that pretargeting via metal chelation is not feasible using this model. However, significant accumulation of “unchelated” 68Ga3+ in the tumour was found (12.9 %ID/g) even without prior administration of THPMe-NCS-huA33, though tumour-to-background contrast was impaired by residual activity in the blood. Therefore, the 68Ga-only experiment was repeated using THPMe (20 μg, 1 h after 68Ga3+ administration) to clear circulating 68Ga3+, producing a three-fold improvement of the tumour-to-blood activity concentration ratio. Although preliminary, these results highlight the potential of THPMe as a 68Ga clearing agent in imaging applications with gallium citrate.
An organoiridium–albumin bioconjugate (Ir1‐HSA) was synthesized by reaction of a pendant maleimide ligand with human serum albumin. The phosphorescence of Ir1‐HSA was enhanced significantly compared ...to parent complex Ir1. The long phosphorescence lifetime and high 1O2 quantum yield of Ir1‐HSA are highly favorable properties for photodynamic therapy. Ir1‐HSA mainly accumulated in the nucleus of living cancer cells and showed remarkable photocytotoxicity against a range of cancer cell lines and tumor spheroids (light IC50; 0.8–5 μm, photo‐cytotoxicity index PI=40–60), while remaining non‐toxic to normal cells and normal cell spheroids, even after photo‐irradiation. This nucleus‐targeting organoiridium‐albumin is a strong candidate photosensitizer for anticancer photodynamic therapy.
On target: A nucleus‐targeted organo‐iridium‐HSA conjugate for photodynamic therapy has been developed. Phosphorescence of a weakly emissive maleimide‐functionalized Ir complex is greatly enhanced when conjugated to human serum albumin. The iridium‐HSA conjugate targets the nucleus and generates 1O2 for photodynamic therapy upon irradiation with visible light.
The Pt(IV) prodrug
-Pt(pyridine)
(N
)
(OH)
(
) and its coumarin derivative
-Pt(pyridine)
(N
)
(OH)(coumarin-3-carboxylate) (
) are promising agents for photoactivated chemotherapy. These complexes ...are inert in the dark but release Pt(II) species and radicals upon visible light irradiation, resulting in photocytotoxicity toward cancer cells. Here, we have used synchrotron techniques to investigate the in-cell behavior of these prodrugs and visualize, for the first time, changes in cellular morphology and Pt localization upon treatment with and without light irradiation. We show that photoactivation of
induces remarkable cellular damage with extreme alterations to multiple cellular components, including formation of vacuoles, while also significantly increasing the cellular accumulation of Pt species compared to dark conditions. X-ray absorption near-edge structure
XANES) measurements in cells treated with
indicate only partial reduction of the prodrug upon irradiation, highlighting that phototoxicity in cancer cells may involve not only Pt(II) photoproducts but also photoexcited Pt(IV) species.
Metals play vital roles in nutrients and medicines and provide chemical functionalities that are not accessible to purely organic compounds. At least 10 metals are essential for human life and about ...46 other non-essential metals (including radionuclides) are also used in drug therapies and diagnostic agents. These include platinum drugs (in 50% of cancer chemotherapies), lithium (bipolar disorders), silver (antimicrobials), and bismuth (broad-spectrum antibiotics). While the quest for novel and better drugs is now as urgent as ever, drug discovery and development pipelines established for organic drugs and based on target identification and high-throughput screening of compound libraries are less effective when applied to metallodrugs. Metallodrugs are often prodrugs which undergo activation by ligand substitution or redox reactions, and are multi-targeting, all of which need to be considered when establishing structure-activity relationships. We focus on early-stage
in vitro
drug discovery, highlighting the challenges of evaluating anticancer, antimicrobial and antiviral metallo-pharmacophores in cultured cells, and identifying their targets. We highlight advances in the application of metal-specific techniques that can assist the preclinical development, including synchrotron X-ray spectro(micro)scopy, luminescence, and mass spectrometry-based methods, combined with proteomic and genomic (metallomic) approaches. A deeper understanding of the behavior of metals and metallodrugs in biological systems is not only key to the design of novel agents with unique mechanisms of action, but also to new understanding of clinically-established drugs.
The vital roles of metals in nutrients and medicines are not accessible to purely organic compounds.
Novel biotinylated diazido-Pt(iv) complexes exhibit high visible light photocytotoxicity while being stable in the dark. Photocytotoxicity and cellular accumulation of all-trans-Pt(py)
(N
)
...(biotin)(OH) (2a) were enhanced significantly when bound to avidin; irradiation induced dramatic cellular morphological changes in human ovarian cancer cells treated with 2a.