Radiotherapeutics: Harnessing the Power of Radiation for Targeted Therapy and Diagnostic Imaging

What are radiotherapeutics or radiopharmaceuticals?

Radiopharmaceuticals, or medicinal compounds that contain radioactive isotopes, represent a potent and attractive modality for the treatment and/or diagnosis of a wide range of human diseases. While traditional radiotherapy has proven to be a powerful clinical tool, especially in the treatment of many cancers, its utility is limited by the systemic toxicity associated with radiation exposure. The use of radiopharmaceuticals, therefore, further extends the therapeutic potential of this modality by enabling the targeted delivery of radioactivity to specific cells, limiting off-target effects.  Radiopharmaceuticals, also known as radioligands, combine a target-binding ligand with a radioactive particle, such that binding between the ligand and its target directs precise delivery of the radioactive payload. The target-binding component of a radiopharmaceutical can take many forms, including antibodies, nucleic acids, and nanoparticles. Among these types, clinical interest has been particularly drawn to small-molecule radioligands, which exhibit the superior bioavailability and pharmacokinetics associated with small-molecule therapeutics.  As technical and scientific innovations continue to advance the frontiers of drug discovery and development, next-generation small-molecule radiopharmaceuticals represent a compelling clinical option for the effective treatment and diagnosis a diverse array of human diseases.

What radiopharmaceuticals are currently in clinical use?

The most widespread therapeutic application of radioactivity is for the treatment of cancer, in which radiation exposure is used to kill tumor cells or inhibit their growth. Estimates suggest that between 30% and 50% of cancer patients undergo radiation therapy at some point during their treatment, with even higher rates for breast, anal, and esophageal cancers. However, these therapies are associated with significant side effects due to their general organ and tissue toxicity. As a result, the development of targeted radiotherapeutics for cancer treatment has been of considerable interest. For the treatment of metastatic castration-resistant prostate cancer (mCRPC), researchers have targeted the membrane protein prostate-specific membrane antigen (PMSA), which is commonly overexpressed in prostate cancer. These efforts led to the development of 177Lu-PSMA-617, a radioligand that selectively delivers beta-particle radiation to PMSA-expressing tumor cells and has been shown to meaningfully reduce pain severity in mCRPC patients. Other PMSA-targeted therapies have leveraged alternative radiation sources, such as actinium-225and copper-67,  in an attempt to optimize therapeutic efficacy. Other targets of interest for small-molecule radiotherapeutics include fibroblast activation protein (FAP), poly(ADP-ribose) polymerase (PARP), and a variety of membrane proteins. Overall, of the 13 radiopharmaceuticals currently approved worldwide for therapeutic purposes, all are intended for cancer treatment, highlighting the utility of this approach to improve clinical outcomes for oncology patients.

How are radiopharmaceuticals used for diagnostic purposes?

The remaining 54 globally approved radiopharmaceuticals are intended for diagnostic purposes, enabling radioimaging of tumors, the central nervous system, the cardiovascular system, and other relevant clinical targets. In radioimaging, radioactive compounds localize in specific cells, tissues, or areas of interest and can be detected in vivo by techniques such as positron emission tomography (PET) and single-photon emission computed tomography (SPECT). By leveraging this technology, clinicians can detect tumors, evaluate biomarker expression, and predict responsiveness to subsequent treatment. Beyond its oncological applications, radioimaging has been successfully applied towards neurodegenerative disorders, particularly in recent decades. The radioligand [18F]AV-45, for example, effectively labels amyloid (Aβ) depositions to monitor the progression of Alzheimer’s disease, while tau-targeting radioligands exhibit specificity for tau fibrils over their Aβ counterparts. Other radiopharmaceuticals target factors like translocator protein (TSPO) to enable visualization and tracking of neuroinflammation, a known feature of many neurodegenerative conditions.

What services does Momentum Biotechnologies offer to support the discovery and development of radiotherapeutics?

The development of radiotherapeutics poses unique challenges compared to their non-radioactive counterparts. Most significantly, dealing with radioactive compounds requires adherence to specialized protocols to ensure researcher safety and regulatory compliance. These requirements impose both financial and logistical burdens that can be particularly onerous during the early stages of drug discovery and development. In light of these challenges, inductively coupled plasma mass spectrometry (ICP-MS)has emerged as one of the most valuable technologies in radioligand development. This powerful methodology (which we profiled in a previous blog post) can be used to characterize non-radioactive metal conjugates, which are then used to predict the activity of analogous radioligands. In contrast to traditional quantification methods based on scintillation counting, this technique alleviates radiation-associated safety concerns by substituting the radioisotope with a stable isotope or surrogate payload, such as a lanthanide. ICP-MS can quantify specific metals with sub-ppt sensitivity and is compatible with cell culture samples, biofluids (such as plasma, urine, and CSF), and tissue/tumor samples. Because up to 14 ligands can be multiplexed into a single experiment, ICP-MS can markedly increase experimental throughput and reduce the number of animals required for in vivo biodistribution studies. By leveraging this powerful technology, researchers can develop novel radioligand therapeutics with unprecedented efficiency, paving the way for future generations of targeted radiopharmaceuticals.

Ready to learn more about how our ICP-MS services can accelerate your radiotherapeutics research and development? Get in touch

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