Pharmacokinetic and dosimetric evaluation of [177Lu]Lu-FAPI for stromal-targeted radionuclide therapy in triple-negative breast cancer: a preclinical biodistribution and dosimetry study
Abstract
BackgroundTriple-negative breast cancer (TNBC) has limited targeted treatment options and is strongly influenced by stromal biology. This study evaluated [177Lu]Lu-FAPI for fibroblast activation protein-alpha (FAP)-directed tumor microenvironment targeting in TNBC models.Methods[177Lu]Lu-FAPI was assessed using TNBC stromal FAP analysis, radiochemical quality control, in vitro stability, cellular uptake and blocking assays, internalization and retention studies, serial biodistribution, Single-photon emission computed tomography/computed tomography (SPECT/CT), autoradiography, Medical Internal Radiation Dose (MIRD)-based dosimetry, and preliminary systemic and histologic safety evaluation. The DOTA-FAPI-04 precursor (FAPI-4; CAS 2374782-02-0; molecular formula C40H54F2N10O10; molecular weight, 872.92 g/mol) was obtained from a commercial supplier (MedChemExpress, Shanghai, China, Cat. No. HY-130196) with confirmed purity ≥95% via high-performance liquid chromatography (HPLC).ResultsTNBC stroma showed prominent FAP expression with α-SMA co-localization. [177Lu]Lu-FAPI showed radiochemical purity of 98.7% ± 0.8% via radio-HPLC and 96.1% ± 1.2% via radio-thin-layer chromatography (radio-TLC). At 72 h, intact tracer remained at 92.1% ± 2.7% in saline and 83.4% ± 2.9% in serum. Competitive binding assays revealed an IC50 of 12.3 ± 2.1 nM and a Ki of 8.7 ± 1.5 nM for FAP. FAP-positive cancer-associated fibroblast (CAF)-like cells showed blocking-sensitive uptake, progressive internalization, and prolonged retention. Tumor uptake persisted through 72 h, while blood activity declined to 0.02%ID/g. SPECT/CT and autoradiography confirmed FAP-associated tumor localization. Revised dosimetry estimated absorbed dose as 0.73 ± 0.15 mGy/MBq for tumor and 4.83 ± 0.52 mGy/MBq for the kidney. The tumor-to-kidney absorbed-dose ratio was 0.15, confirming the kidney as the primary organ-at-risk consideration.Conclusions[177Lu]Lu-FAPI showed stromal-targeted TNBC localization and feasible preclinical dosimetry, with the kidney remaining the main organ-at-risk consideration. These findings establish the pharmacokinetic and dosimetric foundation for [177Lu]Lu-FAPI in TNBC; however, therapeutic efficacy remains to be demonstrated in future studies.
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BibTeX
@article{tang2026pharmacokinetic,
title = {{Pharmacokinetic and dosimetric evaluation of [177Lu]Lu-FAPI for stromal-targeted radionuclide therapy in triple-negative breast cancer: a preclinical biodistribution and dosimetry study}},
author = {Zhihua Tang and Lushan Yu and Ke Zhang},
journal = {Frontiers in Oncology},
year = {2026},
month = nov,
doi = {10.3389/fonc.2026.1958236},
url = {https://www.frontiersin.org/articles/10.3389/fonc.2026.1958236},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Pharmacokinetic and dosimetric evaluation of [177Lu]Lu-FAPI for stromal-targeted radionuclide therapy in triple-negative breast cancer: a preclinical biodistribution and dosimetry study
AU - Zhihua Tang
AU - Lushan Yu
AU - Ke Zhang
PY - 2026
DA - 2026/11/04
JO - Frontiers in Oncology
DO - 10.3389/fonc.2026.1958236
UR - https://www.frontiersin.org/articles/10.3389/fonc.2026.1958236
AB - BackgroundTriple-negative breast cancer (TNBC) has limited targeted treatment options and is strongly influenced by stromal biology. This study evaluated [177Lu]Lu-FAPI for fibroblast activation protein-alpha (FAP)-directed tumor microenvironment targeting in TNBC models.Methods[177Lu]Lu-FAPI was assessed using TNBC stromal FAP analysis, radiochemical quality control, in vitro stability, cellular uptake and blocking assays, internalization and retention studies, serial biodistribution, Single-photon emission computed tomography/computed tomography (SPECT/CT), autoradiography, Medical Internal Radiation Dose (MIRD)-based dosimetry, and preliminary systemic and histologic safety evaluation. The DOTA-FAPI-04 precursor (FAPI-4; CAS 2374782-02-0; molecular formula C40H54F2N10O10; molecular weight, 872.92 g/mol) was obtained from a commercial supplier (MedChemExpress, Shanghai, China, Cat. No. HY-130196) with confirmed purity ≥95% via high-performance liquid chromatography (HPLC).ResultsTNBC stroma showed prominent FAP expression with α-SMA co-localization. [177Lu]Lu-FAPI showed radiochemical purity of 98.7% ± 0.8% via radio-HPLC and 96.1% ± 1.2% via radio-thin-layer chromatography (radio-TLC). At 72 h, intact tracer remained at 92.1% ± 2.7% in saline and 83.4% ± 2.9% in serum. Competitive binding assays revealed an IC50 of 12.3 ± 2.1 nM and a Ki of 8.7 ± 1.5 nM for FAP. FAP-positive cancer-associated fibroblast (CAF)-like cells showed blocking-sensitive uptake, progressive internalization, and prolonged retention. Tumor uptake persisted through 72 h, while blood activity declined to 0.02%ID/g. SPECT/CT and autoradiography confirmed FAP-associated tumor localization. Revised dosimetry estimated absorbed dose as 0.73 ± 0.15 mGy/MBq for tumor and 4.83 ± 0.52 mGy/MBq for the kidney. The tumor-to-kidney absorbed-dose ratio was 0.15, confirming the kidney as the primary organ-at-risk consideration.Conclusions[177Lu]Lu-FAPI showed stromal-targeted TNBC localization and feasible preclinical dosimetry, with the kidney remaining the main organ-at-risk consideration. These findings establish the pharmacokinetic and dosimetric foundation for [177Lu]Lu-FAPI in TNBC; however, therapeutic efficacy remains to be demonstrated in future studies.
SN - 2234-943X
ER -