Repurposing carboplatin-based Pt(IV)-deferoxamine conjugates for infection theranostics

Abstract

Recently, multifunctional platinum(IV) complexes designed as prodrugs for the anticancer drug carboplatin and the iron chelator deferoxamine (DFO), each featuring a DFO unit at one axial position and either hemisuccinate or acetate at the other, were developed. As these compounds contain DFO, they hold the potential to be radiolabelled with gallium-68 for molecular imaging and to be recognized by microorganisms, which can utilise DFO as a siderophore-based iron source being taken up by specific siderophore transporters (SITs). Combining this recognition mechanism with a cytotoxic carboplatin core, these compounds could potentially lead to specific antimicrobial activity, particularly against Aspergillus fumigatus (AFU), which causes systemic infections and expresses relevant SITs. The two complexes were radiolabelled with gallium-68 and evaluated for radiochemical purity and protein binding, exhibiting quantitative ⁶⁸Ga-labeling yields with high radiochemical purity and stability in human serum as well as low protein binding. In vitro uptake assays in AFU and AFU mutants lacking SITs were performed as well as MIC assays for assessment of antifungal activity in comparison to DFO and carboplatin alone. Complexes were also evaluated in in vivo assays including stability studies in healthy mice as well as biodistribution studies and PET imaging in a rat pulmonary aspergillosis model, revealing favourable pharmacokinetics with rapid distribution and a renal excretion pattern with pronounced accumulation in AFU infected lung tissue. However, rapid metabolism of the complexes was observed already 5 min p.i. in serum and urine samples. Overall, this study demonstrates the potential of carboplatin-based Pt(IV)-DFO conjugates for application in infection theranostics.