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Updated: Mar 20, 2026
![Automated Preparation of [68Ga]Ga-3BP-3940 on a Synthesis Module for PET Imaging of the Tumor Microenvironment](/_next/image?url=https%3A%2F%2Fcloudfront.jove.com%2FCDNSource%2Fteasers%2F68356.jpg&w=3840&q=50)
Automated Preparation of [68Ga]Ga-3BP-3940 on a Synthesis Module for PET Imaging of the Tumor Microenvironment
Published on: April 25, 2025
Sequential FAP and Mitochondria-Targeting Radioconjugate with High Tumor Uptake Efficiency and Long Retention Time
Guoyu Wang1, Fanglei Zhang1, Daojia Liu1
1Department of Nuclear Medicine, Department of Radiation Oncology, Clinical Oncology School of Fujian Medical University, NHC Key Laboratory of Cancer Metabolism, Fujian Cancer Hospital, Fuzhou 350014, China.
Abstract:
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.
Insights
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.
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.
![An Automated Radiosynthesis of [68Ga]Ga-FAPI-46 for Routine Clinical Use](/_next/image?url=https%3A%2F%2Fcloudfront.jove.com%2FCDNSource%2Fteasers%2F66708.jpg&w=3840&q=50)