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Radiometal-Labeled Photoactivatable Pt(IV) Anticancer Complex for Theranostic Phototherapy

2023.08.29.

Cinzia Imberti et al., Inorganic Chemistry, 2023

Summary

Inorganic compounds, typically in the form of metals or minerals, have been used in medicine for centuries, but it was the discovery of the antiproliferative platinum compound cisplatin in the 1960s that ignited considerable interest in the development of metal-based drugs in the following decades. However, this substantial research effort has led to only a few successful clinical agents so far, mainly because lack of targeting and consequent severe side effects have hampered the translation of novel metallodrugs toward clinical use.
Light-activated metallodrugs provide spatial and temporal control of their cytotoxic activity by using visible light irradiation to achieve selective activation in the target tissue. Photodynamic therapy (PDT) uses photosensitizers, which can be excited by visible light irradiation to a long-lived triplet state. In this state, they can interact with molecular oxygen to yield the highly reactive singlet oxygen, which is responsible for their photocytotoxicity. These agents are catalytic, as upon energy transfer to molecular oxygen the photosensitizer is de-excited to its ground state and available to perform another cycle. However, their intrinsic dependence on tissue oxygenation can be problematic in hypoxic tumors, which can become resistant to treatment.
Alternatively, light-activated metallodrugs may undergo chemical reactions upon light irradiation (photoactivation) to form cytotoxic species. Photoactivatable azido Pt(IV) agents are stable in the dark but can be reduced to cytotoxic Pt(II) species by visible light irradiation with concomitant release of azidyl radicals. Although this mechanism of action is unavoidably noncatalytic, it is oxygen-independent and promising for treatment of hypoxic cancers. Prototype azido Pt(IV) agent (trans,trans,trans-[Pt(pyridine)2(N3)2(OH)2]) Pt1 is photocytotoxic in a range of cancer cell lines, irrespective of their sensitivity to cisplatin, suggesting a different mechanism of action. Platinum(IV) azido agents have been previously functionalized at the axial hydroxido ligand position to introduce peptides and proteins as targeting vectors, as well as other cytotoxic agents for multitargeting action, all without disrupting their photoactivation ability.
Imaging is a powerful tool to understand the biological behavior of drugs in cells and in vivo and to select promising candidates for preclinical development toward clinical translation. For light-activated agents, imaging can also guide the development of treatment protocols by identifying the optimum time for light-irradiation of the target cells/tissue based on the accumulation of the phototherapeutics.
In vitro fluorescence imaging has been extensively used to map luminescent Ru(II) and Ir(III) photosensitizers in cancer cells. Metal specific techniques, such as LA-ICP-MS or XRF, can be used to determine the accumulation and intracellular localization of the metal center in cancer cells. Recently, we have utilized synchrotron-XRF to visualize platinum from Pt1 and its coumarin derivative in prostate cancer cells. While these techniques can also be applied ex vivo, as was shown by Rompel who imaged cancer tissue from xenograft models treated with gallium and ruthenium metallodrugs, they do not allow imaging in vivo.
Radionuclide imaging provides an effective way to track the fate of a molecule in vivo by exploiting a radioactive label. This approach has been previously utilized for PDT agents based on porphyrins and other tetrapyrrole derivatives. Radiolabeling of a porphyrin derivative has been previously performed using PET radionuclides 18F or 124I, but most commonly, the tetrapyrrole unit was radiolabeled with a radiometal, either directly in the tetrapyrrole ring (e.g., 68Ga or 64Cu), or by introducing a chelating fragment into the structure, able to bind radiometals to generate a theranostic agent. To the best of our knowledge, no examples of radiolabeled photoactivated chemotherapeutic (PACT) agents have been reported in the literature so far.
Deferoxamine (DFO, desferrioxamine) is a siderophore used by bacteria to acquire iron from their surroundings. DFO is clinically utilized to treat iron overload but has also gained popularity as a chelator for the PET radiometal 89Zr. Owing to its similarity to Fe(III) in ionic radius, oxidation state, and coordination preferences, Ga(III) can also be coordinated efficiently by DFO, and 68Ga radiolabeling of DFO occurs in mild conditions. Interestingly, besides providing a way to incorporate a radiometal in photoactivatable Pt(IV) complexes, DFO also displays interesting biological properties: it has been previously investigated as an anticancer treatment and was recently found to enhance the cytotoxic activity of cisplatin and carboplatin when used in combination with these agents. DFO conjugates of Pt(IV) carboplatin prodrugs have also been recently evaluated for their cytotoxic activity in cancer cells but were found to be less effective than either DFO or carboplatin alone.
Here, the authors describe the synthesis of Pt-succ-DFO, a novel light-activated Pt(IV)-azido complex with a pendant DFO for radiometal chelation, and its corresponding heterobimetallic derivatives obtained by complexation with Fe(III) and Ga(III). The authors then report the photophysical properties and phototherapeutic potential of these agents in comparison with parent complex Pt1, to evaluate the effect of the axial succ-DFO ligand and its complexation with Ga(III) or Fe(III). Finally, they utilize the 68Ga-labeled derivative, Pt-succ-DFO-68Ga, to determine the serum stability of Pt-succ-DFO-Ga and its in vivo biodistribution in healthy animals.

Results from the and nanoScan PET/CT

For the imaging studies, dynamic PET scanning was performed using a nanoPET/CT (Mediso Medical Imaging Systems). 4 female balb/C mice (7–9 weeks) were anesthetized with isoflurane (O2 flow rate of 1.0–1.5 L/min and isoflurane levels of 2–2.5%), cannulated at the tail vein using a catheter (27G), and placed on the scanner bed. The bed was heated to 37 °C by internal air flow to keep the animal at normal body temperature, and the respiration rate was monitored throughout scanning. A semicircular CT scan (55 kVp X-ray source, 600 ms exposure time in 180 projections) was performed, followed by a 120-min PET scan (1:5 coincidence mode; 5 ns coincidence time window). Pt-succ-DFO-68Ga (ca. 4 MBq in 100 μL of saline) was injected at the start of the PET scan. PET and CT data sets were reconstructed using the Monte Carlo-based full 3D iterative algorithm Tera-Tomo (Mediso Medical Imaging Systems) with the following settings for PET reconstruction: 4 iterations, 6 subsets, 1–3 coincidence mode, voxel sized 0.4 mm (isotropic), energy window 400–600 keV with attenuation, and scatter correction and binned into several frames (5 × 2 min, 4 × 5 min, 6 × 15 min). All reconstructed data sets were analyzed using VivoQuant 1.21 software (inviCRO).
Figure 4. shows the biodistribution of Pt-succ-DFO-68Ga was measured in healthy mice by using dynamic PET imaging. The PET images and resulting time-activity curves show that most of the Pt-succ-DFO-68Ga was quickly excreted through the kidneys into the urine with minimal accumulation in any tissue. A minor portion of the radiolabeled product was excreted via the hepatobiliary route, as was also confirmed by the ex vivo biodistribution performed at 2 h after injection where some accumulation in the gastrointestinal tract (particularly bile and small intestine) was visible, particularly for 2 of the 4 animals
.
Figure S11. shows the MIP images of Pt-succ-DFO68Ga biodistribution in three healthy animals at different
time points after injection. H = heart, K = kidney, B = bladder, GB = gallbladder, I = intestine. 

  • The authors have developed a novel photoactivatable Pt(IV) azido agent that can incorporate the PET radionuclide 68Ga. 
  • They utilized the resulting radiolabeled Pt-succ-DFO-68Ga complex to image, for the first time, the in vivo behavior of this promising class of platinum phototherapeutics. Pt-succ-DFO-68Ga was stable in serum and displayed a promising biodistribution profile with rapid renal excretion and low tissue accumulation, encouraging further preclinical development of photoactivatable Pt(IV) azido agents, particularly those conjugated to cancer-targeting molecules.
  • More generally, this work serves as a proof of concept to demonstrate the utility of radiolabeling and radionuclide imaging to investigate the properties of photoactivatable agents, thus facilitating their preclinical development and ultimately their clinical translation.

Full article on pubs.acs.org

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