- All four Pt(IV)-DFO complexes achieved quantitative 68Ga labelling, >95% radiochemical purity, and excellent stability in aqueous buffer and human serum at 1 hour.
- Pharmacokinetics were dictated by hydrophilicity or lipophilicity, showing renal or hepatobiliary clearance; tumour uptake was low but tumour-to-healthy ratios reached 4.5 at 55 minutes.
- In vivo ester hydrolysis generated [68Ga]Ga-1 (DFO-succinic acid), causing variable systemic stability; [68Ga]Ga-D showed best tumour retention, contrast and pharmacokinetic profile.
Eur J Med Chem. 2026 Sep 3;320:119302. doi: 10.1016/j.ejmech.2026.119302. Online ahead of print.
ABSTRACT
Pt (IV) complexes have emerged as promising redox-activated prodrugs with improved pharmacological properties compared to Pt(II) and the potential for functionalising additional binding sites. In this study, four Pt(IV)-deferoxamine (DFO) complexes (A-D) were evaluated as gallium-68 radiolabelled imaging agents in healthy mice and in a murine osteosarcoma model using positron emission tomography (PET). All complexes presented quantitative 68Ga-labelling yields with high radiochemical purity (>95%) and excellent stability in aqueous buffer and human serum after 1h incubation. In vivo evaluation in naïve mice demonstrated that pharmacokinetics of the complexes were largely governed by their hydrophilicity and lipophilicity, displaying predominant renal or hepatobiliary clearance, respectively. In the orthotopic osteosarcoma model, the complexes showed tumour-to-healthy tissue ratios ranging from 1.1 ± 0.7 to 4.5 ± 3.2 at 55 min post-injection. Ex vivo biodistribution confirmed relatively low tumour uptake, ranging from 0.3 ± 0.1 to 1.1 ± 0.9%IA/g at 60 min post-injection. Radio-metabolite studies revealed in vivo formation of chelator [68Ga]Ga-1 (DFO-succinic acid), consistent with ester bond hydrolysis, with variable systemic stability across all complexes. Cellular radioFlow analysis of [68Ga]Ga-D accumulation in tumours confirmed predominant retention in tumour and stromal cells. Among the investigated complexes, [68Ga]Ga-D provided the highest tumour-to-background contrast with the most desirable pharmacokinetic profile and in vivo stability, making it the most promising candidate for future studies. Overall, these results demonstrate that Pt(IV)-DFO complexes retain their in vivo tumour-targeting capabilities, supporting their potential use as PET-based imaging agents for osteosarcoma.
PMID:42710348 | DOI:10.1016/j.ejmech.2026.119302
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