Alpha-peptide receptor radionuclide therapy using actinium-225 labeled somatostatin receptor agonists and antagonists

Mengqi Shi; Vivianne Jakobsson; Lukas Greifenstein; Pek-Lan Khong; Xiaoyuan Chen; Richard P Baum; Jingjing Zhang

doi:10.3389/fmed.2022.1034315

Alpha-peptide receptor radionuclide therapy using actinium-225 labeled somatostatin receptor agonists and antagonists

Front Med (Lausanne). 2022 Dec 7:9:1034315. doi: 10.3389/fmed.2022.1034315. eCollection 2022.

Authors

Mengqi Shi^{1

2}, Vivianne Jakobsson^{1

3}, Lukas Greifenstein⁴, Pek-Lan Khong^{1

5}, Xiaoyuan Chen^{1

2

5

6

7}, Richard P Baum⁴, Jingjing Zhang^{1

2

5}

Affiliations

¹ Department of Diagnostic Radiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
² Nanomedicine Translational Research Program, NUS Center for Nanomedicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
³ Academy for Precision Oncology, International Centers for Precision Oncology (ICPO), Wiesbaden, Germany.
⁴ CURANOSTICUM Wiesbaden-Frankfurt, Center for Advanced Radiomolecular Precision Oncology, Wiesbaden, Germany.
⁵ Clinical Imaging Research Centre, Centre for Translational Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
⁶ Department of Surgery, Chemical and Biomolecular Engineering, and Biomedical Engineering, Yong Loo Lin School of Medicine and College of Design and Engineering, National University of Singapore, Singapore, Singapore.
⁷ Agency for Science, Technology, and Research (ASTAR), Institute of Molecular and Cell Biology, Singapore, Singapore.

Abstract

Peptide receptor radionuclide therapy (PRRT) has over the last two decades emerged as a very promising approach to treat neuroendocrine tumors (NETs) with rapidly expanding clinical applications. By chelating a radiometal to a somatostatin receptor (SSTR) ligand, radiation can be delivered to cancer cells with high precision. Unlike conventional external beam radiotherapy, PRRT utilizes primarily β or α radiation derived from nuclear decay, which causes damage to cancer cells in the immediate proximity by irreversible direct or indirect ionization of the cells' DNA, which induces apoptosis. In addition, to avoid damage to surrounding normal cells, PRRT privileges the use of radionuclides that have little penetrating and more energetic (and thus more ionizing) radiations. To date, the most frequently radioisotopes are β^- emitters, particularly Yttrium-90 (⁹⁰Y) and Lutetium-177 (¹⁷⁷Lu), labeled SSTR agonists. Current development of SSTR-targeting is triggering the shift from using SSTR agonists to antagonists for PRRT. Furthermore, targeted α-particle therapy (TAT), has attracted special attention for the treatment of tumors and offers an improved therapeutic option for patients resistant to conventional treatments or even beta-irradiation treatment. Due to its short range and high linear energy transfer (LET), α-particles significantly damage the targeted cancer cells while causing minimal cytotoxicity toward surrounding normal tissue. Actinium-225 (²²⁵Ac) has been developed into potent targeting drug constructs including somatostatin-receptor-based radiopharmaceuticals and is in early clinical use against multiple neuroendocrine tumor types. In this article, we give a review of preclinical and clinical applications of ²²⁵Ac-PRRT in NETs, discuss the strengths and challenges of ²²⁵Ac complexes being used in PRRT; and envision the prospect of ²²⁵Ac-PRRT as a future alternative in the treatment of NETs.

Keywords: SSTR; SSTR antagonist; actinium-225; neuroendocrine tumor; peptide receptor radionuclide therapy (PRRT); targeted α-particle therapy.

Publication types

Review