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Updated: Apr 6, 2026
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Automated Preparation of [68Ga]Ga-3BP-3940 on a Synthesis Module for PET Imaging of the Tumor Microenvironment
Published on: April 25, 2025
Porphyrins modified fibroblast activation protein inhibitor for enhanced cancer radionuclide therapy
Yadong Wang1, Jiajun Chen1, Xuanyang Li2
1Key Laboratory of Radiation Physics and Technology of the Ministry of Education, Institute of Nuclear Science and Technology, Sichuan University, Chengdu, 610064, PR China.
Abstract:
Fibroblast activation protein (FAP) over-expressed on cancer associated fibroblast represents an attractive pan-target for cancer theranostics. FAP inhibitors (FAPIs) have achieved remarkable success in cancer imaging, but its rapid blood clearance and short tumor retention limited application in radionuclide therapy. Strategies to prolong FAPI derivatives circulation, such as dimerization and albumin binding conjugates, often make limited improvement and increase background uptake. Porphyrins, are widely used as photosensitizers in photodynamic therapy, possess favorable pharmacokinetic properties including prolonged circulation and target to some tumors. Here, for the first time, we proposed integrating respective merits of porphyrin and FAPI to develop new radionuclide deliver system with ideal tumor targeting and retention for high-performance cancer endoradiotherapy. Two lutetium-177 (177Lu) radiolabeled FAPI derivatives, [177Lu]Lu-DOTA-P1-FAPI and [177Lu]Lu-DOTA-P2-FAPI were well developed and characterized, of which the anticancer effects were systematically evaluated. Both radiolabeled FAPI ligands showed excellent stability in vitro and higher specific binding ability toward FAP-positive cancer cells over widely-used 177Lu-DOTA-FAPI-04. Ex vivo biodistribution revealed much higher tumor retention ability of [177Lu]Lu-DOTA-P1-FAPI (111.26 ± 40.65 %ID/g) and [177Lu]Lu-DOTA-P2-FAPI (190.31 ± 91.16 %ID/g) compared to [177Lu]Lu-DOTA-FAPI-04 (3.69 ± 0.19 %ID/g) at 48 h. More importantly, [177Lu]Lu-DOTA-P1-FAPI and [177Lu]Lu-DOTA-P2-FAPI produced much stronger tumor growth inhibition and longer median survival in murine xenograft models than [177Lu]Lu-DOTA-FAPI-04 with equal dosage. The outcome of this work demonstrated that porphyrin modification allows a new development path and research perspective for FAPI radiopharmaceutical clinical translation.
Insights
This study introduces novel porphyrin-modified FAP inhibitors (FAPI) for enhanced cancer radionuclide therapy. These new agents demonstrate superior tumor retention and potent anticancer effects compared to existing FAPIs.
Area of Science:
- Nuclear Medicine
- Oncology
- Radiopharmaceutical Chemistry
Background:
- Fibroblast Activation Protein (FAP) is a target for cancer theranostics.
- Current FAP inhibitors (FAPIs) show promise in imaging but have limitations in radionuclide therapy due to rapid clearance and short tumor retention.
- Porphyrins offer favorable pharmacokinetics and tumor targeting, making them suitable for therapeutic applications.
Purpose of the Study:
- To develop novel FAPI derivatives by integrating porphyrin properties for improved tumor targeting and retention in cancer endoradiotherapy.
- To evaluate the in vitro and in vivo anticancer efficacy of these new radiolabeled FAPI derivatives.
Main Methods:
- Two lutetium-177 (177Lu) radiolabeled FAPI derivatives, [177Lu]Lu-DOTA-P1-FAPI and [177Lu]Lu-DOTA-P2-FAPI, were synthesized and characterized.
- In vitro stability and binding affinity to FAP-positive cancer cells were assessed.
- Ex vivo biodistribution studies in murine xenograft models were performed to evaluate tumor retention.
- Anticancer effects, including tumor growth inhibition and median survival, were evaluated in vivo.
Main Results:
- The novel radiolabeled FAPI ligands exhibited excellent in vitro stability and higher specific binding to FAP-positive cancer cells compared to 177Lu-DOTA-FAPI-04.
- [177Lu]Lu-DOTA-P1-FAPI and [177Lu]Lu-DOTA-P2-FAPI demonstrated significantly higher tumor retention at 48 hours post-injection compared to 177Lu-DOTA-FAPI-04.
- Both novel agents induced stronger tumor growth inhibition and prolonged median survival in murine models than 177Lu-DOTA-FAPI-04 at equivalent doses.
Conclusions:
- Porphyrin modification of FAPI represents a promising strategy to enhance tumor targeting and retention for effective cancer endoradiotherapy.
- The developed [177Lu]Lu-DOTA-P1-FAPI and [177Lu]Lu-DOTA-P2-FAPI show potential for clinical translation in FAP-targeted radionuclide therapy.
- This approach opens new avenues for developing advanced radiopharmaceuticals for cancer treatment.
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