Development and Characterization of Novel FAP-Targeted Theranostic Pairs: A Bench-to-Bedside Study

Wei Huang; Yizhen Pang; Qiufang Liu; Chenyi Liang; Shuxian An; Qianyun Wu; You Zhang; Gang Huang; Haojun Chen; Jianjun Liu; Weijun Wei

doi:10.34133/research.0282

Development and Characterization of Novel FAP-Targeted Theranostic Pairs: A Bench-to-Bedside Study

Research (Wash D C). 2023 Nov 28:6:0282. doi: 10.34133/research.0282. eCollection 2023.

Authors

Wei Huang¹, Yizhen Pang², Qiufang Liu³, Chenyi Liang¹, Shuxian An¹, Qianyun Wu¹, You Zhang¹, Gang Huang¹, Haojun Chen², Jianjun Liu¹, Weijun Wei^{1

2

3}

Affiliations

¹ Department of Nuclear Medicine, Institute of Clinical Nuclear Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China.
² Department of Nuclear Medicine and Minnan PET Center, Xiamen Cancer Center, Xiamen Key Laboratory of Radiation Oncology, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361003, China.
³ Department of Nuclear Medicine, Fudan University Shanghai Cancer Center, Fudan University, Shanghai 200032, China.

Abstract

Fibroblast activation protein (FAP) is among the most popular targets in nuclear medicine imaging and cancer theranostics. Several small-molecule moieties (FAPI-04, FAPI-46, etc.) are used for developing FAP-targeted theranostic agents. Nonetheless, the circulation time of FAP inhibitors is relatively short, resulting in rapid clearance via kidneys, low tumor uptake, and associated unsatisfactory treatment efficacy. To address the existing drawbacks, we engineered 3 peptides named FD1, FD2, and FD3 with different circulation times through solid-phase peptide synthesis. All the 3 reported peptides bind to human and murine FAP with single-digit nanomolar affinity measured by surface plasmon resonance. The diagnostic and therapeutic potential of the agents labeled with ⁶⁸Ga and ¹⁷⁷Lu was assessed in several tumor models exhibiting different levels of FAP expression. While radiolabeled FD1 was rapidly excreted from kidneys, radiolabeled FD2/FD3 have significantly prolonged circulation, increased tumor uptake, and decreased kidney accumulation. Our findings indicated that [⁶⁸Ga]Ga-DOTA-FD1 positron emission tomography (PET) effectively detected FAP dynamics, whereas [¹⁷⁷Lu]Lu-DOTA-FD2 and [¹⁷⁷Lu]Lu-DOTA-FD3 exhibited remarkable therapeutic efficacy in FAP-overexpressing tumor models, including pancreatic cancer cell models characterized by abundant stroma. Moreover, a pilot translational investigation demonstrated that [⁶⁸Ga]Ga-DOTA-FD1 had the capability to identify both primary and metastatic tumors with precision and distinction. In summary, we developed [⁶⁸Ga]Ga-DOTA-FD1 for same-day PET imaging of FAP dynamics and [¹⁷⁷Lu]Lu-DOTA-FD2 and [¹⁷⁷Lu]Lu-DOTA-FD3 for effective radioligand therapy of FAP-overexpressing tumors.