Sequential FAP and Mitochondria-Targeting Radioconjugate with High Tumor Uptake Efficiency and Long Retention Time for Radiopharmaceutical Therapy

Fibroblast activation protein inhibitors (FAPIs) have
transformed
cancer imaging, yet their therapeutic potential remains limited by
rapid tumor clearance. To overcome this barrier, we introduce a mitochondria-targeted
FAPI derivative, FAPI-PEG3-K-TPP, designed for sequential
targeting: initial FAP binding, followed by subcellular localization
to mitochondria. Constructed by conjugating a triphenylphosphonium
(TPP) moiety to FAPI-46 via a flexible PEG3-K linker, the
agent was efficiently radiolabeled with 68Ga and 177Lu, exhibiting high radiochemical purity (>95%), yield (>95%),
stability,
and dual targeting specificity. In vivo SPECT studies revealed tumor
retention exceeding 120 hdramatically longer than the <48
h observed with FAPI-46along with enhanced tumor uptake and
potent suppression of tumor growth by the 177Lu-labeled
complex. This work establishes mitochondrial sequestration as a powerful
strategy to augment targeted radionuclide therapy and opens avenues
for theranostic applications of organelle-targeted radiopharmaceuticals.