Self-Assembling Amphiphilic Dendrimers (SAADs) for the Detection of CXCR4⁺ Tumors by PET imaging.

Self-assembling amphiphilic dendrimers (SAADs) were functionalized to develop a novel CXCR4 targeting PET. The amphiphilic dendrimer- NOTA (1, 4, 7-triazacyclononane-1,4,7-triacetic acid) (C18-NOTA) was combined with the CXCR4 antagonist R54 (C18-PEG4-R54) and four formulations with increasing R54 content (F1–F4) and corresponding non-targeted molecules (F5–F6) were synthetized. F1-F6 and Ga [Ga (III)] derivatives F1-F4 displayed nanomolar affinity for the receptor, with the IC50 decreasing from Ga-F1 to Ga-F4 according to R54 presence. Interestingly, Ga-F1-F4 showed comparable physicochemical properties, with sizes around 16–18 nm and similar positive surface charges. PET imaging and biodistribution studies revealed specific in vivo accumulation in CHO-hCXCR4 tumor–bearing mice for [⁶⁸Ga]Ga-F3. The absence of active targeting for [⁶⁸Ga]Ga-F4, despite its highest R54 density and receptor affinity, suggests that both, ligand density and spatial presentation, play key roles in effective receptor engagement and tumor targeting. Taken together, the results establish CXCR4-targeted SAADs as a promising platform for PET imaging and advance the broader potential of multivalent dendrimer-based tracers.