Development of radiopharmaceuticals for targeted alpha therapy: Where do we stand?

Abstract

Targeted alpha therapy is an oncological treatment, where cytotoxic doses of alpha radiation are locally delivered to tumor cells, while the surrounding healthy tissue is minimally affected. This therapeutic strategy relies on radiopharmaceuticals made of medically relevant radionuclides chelated by ligands, and conjugated to targeting vectors, which promote the drug accumulation in tumor sites. This review discusses the state-of-the-art in the development of radiopharmaceuticals for targeted alpha therapy, breaking down their key structural components, such as radioisotope, targeting vector, and delivery formulation, and analyzing their pros and cons. Moreover, we discuss current drawbacks that are holding back targeted alpha therapy in the clinic, and identify ongoing strategies in field to overcome those issues, including radioisotope encapsulation in nanoformulations to prevent the release of the daughters. Lastly, we critically discuss potential opportunities the field holds, which may contribute to targeted alpha therapy becoming a gold standard treatment in oncology in the future.

The Future of (Radio)‐Labeled Compounds in Research and Development within the Life Science Industry

“…After the FDA approval of Ra‐223 dichloride [70] (commercially available as Xofigo, Bayer AG), for treatment of bone metastases, targeted alpha‐therapy (TAT) has emerged as powerful tool for treating late‐stage cancers for which therapeutic options are limited [71,72] . In the last decade, over a dozen alpha‐emitting radiopharmaceutical conjugates using radionuclides such as Ac‐225, Pb‐212, Th‐227, Bi‐213, and At‐211 have entered clinical trials, supported by encouraging preclinical data [73] . As attention has to be paid to dosimetry considerations and thorough patient selection, concomitant imaging is a key requirement to ensure correct dosing to mitigate the risk for patients [74,75] …”

“…[71,72] In the last decade, over a dozen alpha-emitting radiopharmaceutical conjugates using radionuclides such as Ac-225, Pb-212, Th-227, Bi-213, and At-211 have entered clinical trials, supported by encouraging preclinical data. [73] As attention has to be paid to dosimetry considerations and thorough patient selection, concomitant imaging is a key requirement to ensure correct dosing to mitigate the risk for patients. [74,75] After many years of poor attention, the impressive clinical successes of first targeted radionuclide therapies have led to an exponential global expansion of radiotheranostics, particularly in oncology, and to a multitude of collaborations between academic institutions and pharma companies-startups as well as "big pharma".…”

Die Zukunft (Radio‐)‐isotopenmarkierter Verbindungen in Forschung und Entwicklung der modernen Lebenswissenschaften

“…[71,72] In den letzten zehn Jahren wurden mehr als ein Dutzend Alphastrahlen emittierende, radiopharmazeutische Konjugate mit Radionukliden wie Ac-225, Pb-212, Th-227, Bi-213 und At-211 in die klinische Erprobung gebracht, unterstützt durch vielversprechende präklinische Daten. [73] Da die Dosimetrie und die sorgfältige Auswahl der Patienten beachtet werden müssen, ist die begleitende Bildgebung eine wichtige Voraussetzung für die korrekte Dosierung, um das Risiko für die Patienten zu minimieren. [74,75] Nach vielen Jahren mangelnder Aufmerksamkeit haben die beeindruckenden klinischen Erfolge der ersten zielgerichteten Radionuklidtherapien zu einer exponentiellen weltweiten Expansion der Radiotheranostik geführt, insbesondere in der Onkologie, und zu einer Vielzahl von Kooperationen zwischen akademischen Einrichtungen und Pharmaunternehmen (Biotech Start-ups als auch "Big Pharma").…”

Development of the occupational exposure during the production and application of radiopharmaceuticals in Germany

“…The primary clinical use is focused on 223 Ra, while clinical trials are primarily conducted on 225 Ac and 227 Th. Meanwhile, ligands linked to 212 Bi, 213 Bi, 212 Pb, and 211 At are currently under trial too (Pallares andAbergel 2022, Zhang et al 2023). Additionally, research and application intensively handle radionuclides that enable the production of a radionuclide generator.…”