PET Imaging of Self-Assembled [18F]-Labelled Pd2L4 Metallacages for Anticancer Drug Delivery

Cosialls et al.

In this study by Cosialls et al., the β-CUBE has been used to assess in vivo whole-body biodistribution of 18F-L1 and 18F-C1 cages non-invasively and in a quantitative manner.

Research question

Self-assembled porous metallacages are attractive supramolecular coordination complexes with various applications in medicine, including drug delivery, imaging, and the development of novel theranostic platforms. A palladium-based metallacage scaffold [Pd2L4]4+ has been developed as a potential delivery system for the anticancer drug cisplatin. Encapsulation of cisplatin in integrin-targeted metallacages reduces nephrotoxicity and shows higher in vitro cytotoxicity against cancer cells. However, in-vivo imaging studies of these supramolecular entities are scarce, and their design as novel theranostic platforms is still in its infancy. In vivo Positron Emission Tomography (PET) imaging might offer insights into the structural integrity of metallacages upon in-vivo injection.



The synthesis of an azide precursor was characterized using various spectroscopic techniques. Ligands L1 and L2 were synthesized using specific azide-functionalized substrates. Synthesis of metallacages C1 and C2 involved the reaction of AMBF3-containing ligands with Pd(NO3)2, and the resulting products were characterized using NMR, FTIR, and high-resolution electrospray mass spectrometry (HR-ESIMS). Ligand L1 was radiolabelled with fluorine-18 and was followed by the subsequent formation of 18F-C1, along with the encapsulation of cisplatin in 18F-C1. Quality control of 18F-L1 was performed via analytical radio-HPLC. In vivo and ex vivo biodistribution studies were conducted in female mice using 18F-L1, 18F-C1, and cisplatin-loaded 18F-C1. PET-CT imaging and gamma counting were used for analysis, and statistical tests were performed to assess differences in radioactivity concentrations in various organs at different time points.



The study explored the 18F-labelling of metallacages designed for drug delivery. The study also explored the stability of the cages in the presence of cisplatin and their distribution in vivo through PET imaging and biodistribution studies in healthy mice. The 18F-L1 and 18F-C1 cages retained the ability to encapsulate cisplatin, confirmed by various analyses. The 18F-L1 and 18F-C1 cages  retained the ability to encapsulate cisplatin. PET imaging showed distinct biodistribution profiles between the labeled cages and free ligands, suggesting cage disassembly in vivo, especially with cisplatin encapsulation. The findings suggest that the biodistribution of the injected metallacages differs from that of the free ligands, and cisplatin encapsulation may lead to cage disassembly in vivo.

The obtained results show that 18F-L1 and 18F-C1 that 18F-L1 and 18F-C1 cages  when injected, accumulate in different organs with respect to their ligands in the early time points. Moreover, encapsulation of cisplatin promotes cage disassembly in vivo, as suggested by PET. However, further optimization of the ligand system is needed. Furthermore, the cisplatin encapsulation process also requires in-depth investigation and should be performed on targeted and more hydrophilic cage systems. Overall, owing to their unique physicochemical properties, metal-coordinated supramolecular self-assemblies, including the selected metallacages, can bridge the boundary between traditional inorganic and organic materials. This research contributes to advancing their design for biomedical applications. Additional optimization and investigations are needed for the development of robust cage complexes for potential biomedical applications. In the future, these cages could be used as novel theranostic platform featuring both therapeutic and imaging modalities. However, this is still in its infancy.