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

Guoyu Wang1, Fanglei Zhang1, Daojia Liu1

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Journal of Medicinal Chemistry
|March 18, 2026
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Summary

Scientists developed a new mitochondria-targeted Fibroblast Activation Protein Inhibitor (FAPI) derivative that significantly improves tumor retention and therapeutic efficacy in cancer models. This novel approach enhances targeted radionuclide therapy by localizing drugs within cancer cell mitochondria.

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Area of Science:

  • Oncology
  • Radiochemistry
  • Molecular Imaging

Background:

  • Fibroblast Activation Protein Inhibitors (FAPI) are crucial for cancer imaging but suffer from rapid tumor clearance, limiting therapeutic use.
  • Targeted radionuclide therapy requires agents with prolonged tumor retention for optimal efficacy.

Purpose of the Study:

  • To develop a mitochondria-targeted FAPI derivative to enhance tumor retention and therapeutic outcomes.
  • To investigate the potential of subcellular organelle sequestration for improving targeted radionuclide therapy.

Main Methods:

  • A novel FAPI derivative, FAPI-PEG3-K-TPP, was synthesized by conjugating a triphenylphosphonium (TPP) moiety to FAPI-46.
  • The derivative was radiolabeled with 68Ga and 177Lu, and its targeting specificity and stability were evaluated.
  • In vivo SPECT studies were performed to assess tumor retention and uptake of the radiolabeled agent.

Main Results:

  • The FAPI-PEG3-K-TPP agent demonstrated high radiochemical purity (>95%), yield (>95%), and stability.
  • In vivo studies showed significantly prolonged tumor retention (>120 h) compared to the parent FAPI-46 (<48 h).
  • The 177Lu-labeled complex exhibited enhanced tumor uptake and potent tumor growth suppression.

Conclusions:

  • Mitochondrial sequestration is an effective strategy to overcome rapid tumor clearance and enhance targeted radionuclide therapy.
  • This organelle-targeted approach holds promise for advancing theranostic applications in cancer treatment.