Radiotheranostics Using a Novel ²²⁵Ac-Labeled Radioligand with Improved Pharmacokinetics Targeting Prostate-Specific Membrane Antigen

Abstract

225Ac-based radiotheranostics targeting prostate-specific membrane antigen (PSMA) has induced impressive responses in patients with metastatic castration-resistant prostate cancer. To enhance the therapeutic effects of radioligands labeled with 225Ac (half-life: 10 days), a radioligand that shows longer tumor retention would be useful. Here, we designed and synthesized a straight-chain PSMA-targeting radioligand, PSMA–DA1, which includes an (iodophenyl)­butyric acid derivative as an albumin binder (ALB). We performed preclinical evaluations of PSMA–DA1 as a tool for PSMA-targeting radiotheranostics using 111In, 90Y, and 225Ac. [111In]­In-PSMA–DA1 demonstrated significantly greater tumor uptake and retention than a corresponding non-ALB-conjugated compound. In mice, single-photon emission computed tomography performed with [111In]­In-PSMA–DA1 produced clear tumor images, and the administration of [90Y]­Y-PSMA–DA1 or [225Ac]­Ac-PSMA–DA1 inhibited tumor growth. [225Ac]­Ac-PSMA–DA1 had antitumor effects in mice at a lower radioactivity level than [225Ac]­Ac-PSMA-617, which has been reported to be clinically useful. These results indicate that PSMA–DA1 may be a useful PSMA-targeting radiotheranostic agent.

Rational Design and Pharmacomodulation of Protein-Binding Theranostic Radioligands for Targeting the Fibroblast Activation Protein

“…The albumin-binding motif (ABM) for the in vivo “albumin hitchhiking” approach has been used as a reliable strategy for increasing the tumor uptake of radiopharmaceuticals, which may help bolster the use of small-molecule drugs for long-acting therapeutics. − For this purpose, the p -iodophenyl moiety, truncated Evans blue (EB), ibuprofen, and fatty acids have been developed as albumin-binding entities. , Typically, based on the albumin-binding effect, the long-circulating PSMA/folate-targeted radiotracers with appropriate albumin binders offer distinct advantages, including low background interference, enhanced tumor uptake, prolonged tumor residence, and better therapeutic effect. − , Most recently, some studies have attempted to pharmacomodulate FAP-targeted radioligands and have gained considerable headway. , …”

Synthesis and Evaluation of Novel 111In-Labeled Picolinic Acid-Based Radioligands Containing an Albumin Binder for Development of a Radiotheranostic Platform

“…In our previous study, we described a PSMA-targeting radiotheranostic agent (PSMA-DA1), which included a DOTA-based chelator (DOTADG) . [ 111 In]­In-PSMA-DA1 showed a tumor AUC value of 752% ID/g·h, and the administration of [ 225 Ac]­Ac-PSMA-DA1 to LNCaP tumor-bearing mice marked inhibited tumor growth.…”

“…Radiometal-based radiotheranostics has gained much interest as a promising strategy for treating cancer. Of the various chelators used to produce radioligands for radiotheranostics, 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) derivatives, which are macrocyclic chelators, are the most widely used since they can form complexes with a variety of radiometals, including γ-emitters, which are used for single-photon emission computed tomography (SPECT); β + -emitters, which are used for positron emission tomography (PET); and β – - or α-emitters, which are used for targeted radionuclide therapy (TRNT), and exhibit favorable radiolabeling rates and kinetic stability. − In particular, DOTA-based radioligands targeting prostate-specific membrane antigen (PSMA), e.g., PSMA-617 and PSMA-I&T, have been investigated as potentially useful radiotheranostic agents. ,,, In the past few years, DOTA-based PSMA-targeting radioligands labeled with α-emitting radiometals, such as 225 Ac, have shown greater therapeutic efficacy and lower toxicity in normal tissues than β – -emitter-based therapies when they were used to treat metastatic castration-resistant prostate cancer; thus, performing TRNT with α-emitters has attracted much attention as a new treatment for cancer.…”

Legumain-mediated self-assembly of a 131I-labelled agent for targeted radiotherapy of tumors

“…[1][2][3] Targeted radionuclide therapy, which utilized high selective molecules as carriers to deliver radionuclides to tumor cells, has attracted extensive attention. [4][5][6] It has achieved success with tumor-targeting radiopharmaceuticals such as [ 131 I]MIBG and [ 177 Lu]DOTA-TATE, which have been approved by the food and drug administration (FDA) for the clinical use of TRT. 7,8 Different from external beam radiotherapy, TRT involves the precise delivery of a radiolabeled molecule to the diseased region in a targeted manner, and exposing lethal dose of radiation to the tumor site while avoiding damage to normal tissues.…”