Targeted radionuclide therapy (TRT), as an emerging cancer treatment strategy, has received extensive attention from clinicians and the pharmaceutical industry in recent years. Among the existing targets for nuclear medicine, fibroblast activation protein (FAP) stands out due to its tumor-specific high expression and broad-spectrum presence in various cancers. However, the clinical efficacy of the existing FAP targeted radiopharmaceuticals is not satisfactory due to the fast metabolism and short tumor retention time of FAP inhibitors (FAPIs).
Aiming at the key challenges in the development of FAP targeted radiopharmaceuticals, Professor Zhibo Liu's team at the Department of Applied Chemistry, College of Chemistry and Molecular Engineering, Peking University has developed a series of radiopharmaceuticals based on the platform technologies of albumin binders and boron trifluoride modifications1–3. Additionally, they have conducted prospective research on the safety and efficacy of novel self-developed medical isotopes like 213Bi and 212Pb.
The recent research achievements are as follows:
1. The research team has designed a series of organotrifluoroborate linker modified FAPIs, giving them the following unique advantages: (1) an organotrifluoroborate linker can increase the tumor uptake and elongate the tumor retention of FAPIs, resulting in notably higher tumor uptake while the background is clean; (2) facile 18F-radiolabelling for positron emission tomography to guide radiotherapy with α-emitters, which can hardly be traced in general; (3) improving the pharmacokinetics of FAPI for low-dose TRT while reducing side effects.This researchexplored FAP targeted 213Bi nuclide therapy, the 213Bi was first reported by Zhibo Liu's team in China4.The drug successfully inhibited tumor growth in vivo, filling the gap of 213Bi nuclear drug research in China and revealing the unique advantages of short half-life α-nuclides in radiopharmaceuticals discovery and development5.
2. The antibody has the advantages of high affinity, long half-life and high tumor uptake, and is a good match for longer half-life therapeutic radionuclides (e.g., 177Lu, 225Ac). Therefore, the team screened a FAP-targeting antibody (PKU525) for FAP targeted nuclide therapy. Positron emission tomography (PET) with [89Zr]Zr-PKU525 showed a prolonged tumor retention time of up to 14 days and high specificity.[177Lu]Lu-PKU525 demonstrated significant tumor inhibition with low toxicity and side effects, and has good prospects for clinical translation6.
Fig.1 Pharmacokinetics of[89Zr]Zr-PKU525 in tumor-bearing mice.
3. Targeted alpha therapy (TAT) is an emerging method of cancer treatment that utilizes radioactive substances emitting alpha particles. Alpha particles have high linear energy transfer (LET) and relative biological effectiveness (RBE), which allow for precise targeting and potent destruction of cancer cells. 225Ac is a highly promising alpha nuclide isotope that emits four alpha particles and two beta particles in a single decay event. The team has successfully constructed a stable and highly efficient [225Ac]Ac-PKU525 radiolabeling system, which has demonstrated good therapeutic efficacy and safety in several tumor models, with a therapeutic dose of only one-thousandth of that of the relevant β-nucleic drugs7.
In recent years, based on the innovations in the field of FAP targeted radiopharmaceuticals, Liu's team has collaborated with clinical institutions such as Beijing Cancer Hospital, Peking Union Medical College Hospital, Cancer Hospital of the Chinese Academy of Medical Sciences, Xijing Hospital, and the Lanzhou University Second Hospital to conduct translational research.Several drug candidates have entered the industrial development stage. The above research has been supported by the National Natural Science Foundation of China, the Key R&D Program of the Ministry of Science and Technology, Peking University, Beijing National Laboratory for Molecular Sciences, Peking University-Tsinghua University Center for Life Sciences,the Beijing Municipal Natural Science Foundation,Boomray Pharmaceuticals Co., Ltd. and supported byAnalytical Instrumentation Center of Peking University.
Link of the paper:
1.Xu M, Zhang P, Ding J, Chen J, Huo L, Liu Z. 2022;63(6):952-8. doi: 10.2967/jnumed.121.262533.
2.Zhang P, Xu M, Ding J, Chen J, Zhang T, Huo L, Liu Z. 2022;49(6):1985-96. doi: 10.1007/s00259-021-05591-x.
3.Ding J, Xu M, Chen J, Zhang P, Huo L, Kong Z, Liu Z. 2022;19(9):3429-38. doi: 10.1021/acs.molpharmaceut.2c00579.
4.陈俊艺, 刘宇, 徐梦欣, 刘志博. 2022;42(6):330-4. doi: 10.3760/cma.j.cn321828-20220210-00038.
5.Liu Y, Tang H, Song T, Xu M, Chen J, Cui XY, Han Y, Li Z, Liu Z. Eur J Nucl Med Mol Imaging. 2023. doi: 10.1007/s00259-023-06230-3.
6.Xu M, Chen J, Zhang P, Cai J, Song H, Li Z, Liu Z. Eur J Nucl Med Mol Imaging. 2023. doi: 10.1007/s00259-023-06300-6.
7.Song H, Xu M, Cai J, Chen J, Liu Y, Su Q, Li Z, Liu Z. Chem. Biomed. Imaging. 2023. doi: 10.1021/cbmi.3c00067.
