'See what you treat and treat what you see, at a molecular level' (Cit. Heying Duan)
What is Theranostic and Radio-Theranostic?
Theranostics, the future of medicine (?), combines diagnostics and therapeutics into a powerful approach. Derived from "therapeutics" and "diagnostics," it revolutionizes the field by delivering diagnosis and therapy as a single package. By seamlessly integrating these strategies, can save time, money, and reduces biological side effects. The theranostic concept can be applied with several platforms including radio-theranostic, nanotheranostic, magnetotheranostic, and optotheranostic. These utilize radionuclides, nanoparticles, magnetic particles, and optical probes, respectively. Among these, radio-theranostics for cancer have witnessed remarkable advancements.
In cancer radio-theranostics, a radioactive diagnostic drug is administered to identify cancer cells by targeting specific proteins or receptors on their membranes. Subsequently, the same radionuclide is administered with a different radioactive isotope capable of delivering targeted therapy to the tumour and any metastatic sites, aiming to destroy or inhibit cancer cell growth while minimizing harm to healthy tissues. Follow-up imaging with the diagnostic radionuclide assists in evaluating treatment efficacy, offering potential benefits of cost and time savings, along with reduced biological effects.
Radio-theranostic Pairs are key to unlocking treatment advances.
Theranostic pairs utilize identical molecules labelled with either diagnostic (for imaging the tumour) or therapeutic radioactive substances (for delivering a targeted radioactive payload). This precision targeting enables molecularly tailored imaging and treatment. Ideally, a theranostic pair consists of identical molecules carrying two isotopes of the same element, possessing identical pharmacological properties.
Radiopharmaceuticals comprise three components: the radionuclide with diagnostic and/or therapeutic properties, the chelator connecting the radionuclide to the ligand/probe, and the ligand/probe designed to bind specifically to cancer-specific molecular markers. Two main strategies for radiolabelling are:
1) Direct insertion of the radionuclide onto the molecular scaffold
2) Using a spacer to connect the molecule with a chelator.
Each strategy has its advantages and disadvantages, further elaborated in this comprehensive review.
Depending on the radionuclide chosen, the final compound can be used for diagnostic imaging or to effectively target and destroy cancer cells. It's all about harnessing the power of radiation to either visualize or combat the disease.
Figure 1. Graphical representation of the theranostic approach in a nutshell. On the left, a gamma emitting radionuclide is attached to the tumour specific probe for imaging the tumour location and metabolic function. On the right, a radionuclide capable of delivering a powerful but localized dose of ionizing radiation to the target tissue is attached to a copy of the tumour specific ligand used in the diagnostic stage.
Shopping for Radionuclides
Diagnostic
Two techniques are popular for tumour imaging: single photon emission computed tomography/computed tomography (SPECT/CT) and positron emission tomography (PET) in combination with computed tomography (PET/CT) or magnetic resonance imaging (PET/MRI). In contrast to anatomical methods (CT, MRI), PET and SPECT provide molecular diagnostic images, allowing us to visualize the molecular makeup, function and biology of a tumour.
For tumour diagnostics, gamma emitters (e.g., Technetium-99m, Indium-111, Gallium-67) are used in SPECT imaging, while positron emitters (e.g., Fluorine-18, Carbon-11, Gallium-68) are employed in PET imaging. Gamma emitters provide detailed images of tumour activity and localization through gamma rays detected by gamma cameras, while positron emitters offer higher resolution and sensitivity, providing metabolic activity and molecular process information.
Both gamma and positron emitters share desirable characteristics for imaging: high tissue absorption, low energy transfer, and a long radiation range. As a result, they expose patients to low-level radiation while providing a strong signal.
However, there are also some differences to consider. Gamma emitters release gamma rays which are detected with SPECT as they decay, with half-lives ranging from hours to days. This makes them logistically easier to work with. In contrast, positron emitters cause collisions with electrons in the body, emitting dual gamma rays detected during a PET scan. The half-life of positron emitters is much shorter: from 20 minutes to 2 hours. This rapid decay offers a higher resolution at the cost of convenience; an on-site cyclotron is needed for PET imaging to ensure rapid delivery while the emitters still have enough juice left for imaging.
Therapeutic
Ionizing radiation induces deoxyribonucleic acid (DNA) double-strand breaks and subsequent organized cell death through apoptosis. Therefore, choosing the most appropriate radionuclide for directly targeted irradiation is key. The main factors for candidate selection are:
1) Linear energy transfer (LET) – the higher this is, the more damage is done to the target tissue
2) Emission / Penetration range – how much tissue is penetrated by the radiation (measured in microns up to 2 mm)
3) Half-life – ideally 1-2 weeks to extend the therapeutic effect
Beta particles (e.g., 131I, Lutetium-177, Samarium-153, Yttrium-90) are commonly used for therapeutic purposes. Their high energy transfer to tumour cells and short radiation emission range allows effective treatment while sparing surrounding healthy tissues.
Alpha particles (e.g., Radium-223, Actinium-225) possessing very high LET and short path length are gaining attention, with the former receiving approval from the US Food and Drug Administration. Compared to beta emitters, alpha emitters have higher LETs and shorter path lengths (< 100 μm).
Auger electron emitters (e.g., 123I, Indium-111 (111In), Gallium-67 (67Ga), and Technetium-99m (99mTc)) have been explored but are generally less effective and have a path length that is mostly suited to intracellular irradiation. Despite this, 123I and 111In have been used in clinical trials with high doses for neuroendocrine tumours and thyroid diseases.
In addition, radionuclides usually have two or more types of emission with different energy peaks. This characteristic makes certain radioisotopes used for therapy to be suitable for non-diagnostic imaging. This non-diagnostic imaging can be of great utility to obtain post-treatment SPECT/CT imaging to confirm molecular targeting of the treatment, and rule out pharmacologic interference and stunning.
Theranostics and the future (at the University of Antwerp)
Theranostics epitomizes personalized diagnostic and treatment approaches in precision medicine. This targeted therapy approach enables oncologists to treat what they see and see what they treat, despite each tumour possessing a unique molecular profile and requiring a tailored strategy. Theranostics enables the imaging of specific tumour markers, facilitating patient selection and stratification for the most effective treatment.
Its increasing popularity is evident from the rising number of articles referencing theranostics – 4,500 since the turn of the century.
Figure 2. Number of publications about theranostic per year (data retrieved from PudMed).
While challenges exist in accessing advanced theranostic care due to equipment and compound costs and availability, ongoing research holds great promise. Novel targets and improved radiopharmacokinetics are driving the field towards a more refined and personalized approach. Dosimetry developments will refine treatment, enabling personalized treatment doses and cycles instead of a standard that treats some patients too much or too little. Molecular targeted radioligand therapy is on the verge of integration into everyday clinical nuclear medicine practice.
One institution at the forefront of theranostics is the University of Antwerp, where cutting-edge advancements are being made. Their focus lies in applying the theranostic concept to the tumour microenvironment and specifically targeting the protein fibroblast activation protein (FAP). FAP, expressed on stromal cells in the majority of epithelial cancers, presents a promising diagnostic marker and therapeutic target due to its restricted expression in cancer cells and association with poor prognosis.
Driven by the success of FAP-targeted PET radiotracers, the research team is heavily investigating FAP-targeted radiopharmaceutical therapies. This approach not only enables imaging diagnostics but also targeted radionuclide therapy using the same ligand, offering personalized cancer treatment. However, challenges remain, including the rapid washout from tumours and inadequate pharmacokinetics of current FAP ligands.
To tackle these issues, the collaborative efforts of the radiopharmaceutical science team and the medicinal/biological chemistry team, led by Prof Felipe Elvas, Prof Ingrid de Meester and Prof Pieter Van der Veken, respectively, have resulted in the development of FAP-targeting radiotheranostics with optimal pharmacokinetics. The success of their strategy has been so significant that international patent applications have been filed, signalling a major step forward in the field. Stay tuned for updates as the patent becomes public, and exciting developments continue to emerge from this innovative research endeavour.
Interesting articles
Clear and very well-written review on Theranostic https://pubmed.ncbi.nlm.nih.gov/34976584/
Very nice review about macrocyclic chelator https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/ejic.201900706
A comprehensive review of clinical applications https://www.sciencedirect.com/science/article/
Article written by Lorenzo Cianni and edited by Christien Bowman