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
Affiliations
Wei Huang
Department of Nuclear Medicine, Institute of Clinical Nuclear Medicine, Renji Hospital, School of Medicine,
Shanghai Jiao Tong University, Shanghai 200127, China.
Yizhen Pang
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.
Qiufang Liu
Department of Nuclear Medicine, Fudan University Shanghai Cancer Center,
Fudan University, Shanghai 200032, China.
Chenyi Liang
Department of Nuclear Medicine, Institute of Clinical Nuclear Medicine, Renji Hospital, School of Medicine,
Shanghai Jiao Tong University, Shanghai 200127, China.
Shuxian An
Department of Nuclear Medicine, Institute of Clinical Nuclear Medicine, Renji Hospital, School of Medicine,
Shanghai Jiao Tong University, Shanghai 200127, China.
Qianyun Wu
Department of Nuclear Medicine, Institute of Clinical Nuclear Medicine, Renji Hospital, School of Medicine,
Shanghai Jiao Tong University, Shanghai 200127, China.
You Zhang
Department of Nuclear Medicine, Institute of Clinical Nuclear Medicine, Renji Hospital, School of Medicine,
Shanghai Jiao Tong University, Shanghai 200127, China.
Gang Huang
Department of Nuclear Medicine, Institute of Clinical Nuclear Medicine, Renji Hospital, School of Medicine,
Shanghai Jiao Tong University, Shanghai 200127, China.
Haojun Chen
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.
Jianjun Liu
Department of Nuclear Medicine, Institute of Clinical Nuclear Medicine, Renji Hospital, School of Medicine,
Shanghai Jiao Tong University, Shanghai 200127, China.
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.
