Radiotheranostics Gaining Traction as Cancer Therapy

Radioisotopes linked to the same ligand allow for visualization and destruction of cancer cells

Photo portrait of Zahraa Chorghay
Zahraa Chorghay, PhD
Photo portrait of Zahraa Chorghay

Zahraa Chorghay, PhD, specialized in neuroscience during her undergraduate (University of Toronto) and doctoral studies (McGill University). She continues to explore her passion for neuroscience and for making science accessible and inclusive.

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Published:May 09, 2022
|4 min read
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Imagine a molecule that could help you not only visualize the exact location of cancer in the body but also help you destroy that cancer. This is the basis of radioisotope-based therapeutics, or radiotheranostics, an expanding field where a radioisotope is used for targeted therapy based on imaging of the same target area.1

In the ligand-linker-radioisotope design, the target ligand acts as an anchor for the radioisotope.
Today's Clinical lab

While the concept has been around for more than 70 years—beginning with the use of radioactive iodine to diagnose and treat thyroid cancer—radiotheranostics has seen a relative lack of clinical traction compared to other treatment options. However, with advances in radioisotope chemistry and imaging, radiotheranostics is gaining more attention as a cancer therapeutics approach, particularly for cancers that are aggressive or have limited treatment options. The interest in radiotheranostics is evidenced by the numerous scientific publications over the last decade and an entire session dedicated to current and emerging radiotheranostics at the recent American Association for Cancer Research (AACR) annual meeting in March 2022.

Radiotheranostics typically use a ligand-linker-radioisotope design, where the targeting ligand acts as an anchor to enrich the therapeutic radioisotope at the cancer site. The ligand is commonly a peptide, small molecule, or antibody. The radioisotopes linked to the ligand depend on the intended purpose: those used for cancer diagnostic imaging are γ or positron emitters, while those used for cancer therapy are α or β emitters. Key exceptions to the typical design would be free iodine and certain radiomaterials.

CXCR4 is an emerging radiotheranostics target

At the AACR session, researchers discussed an emerging target of radiotheranostics for hematological and solid cancers. Rudolf Werner from the University of Würzburg, Germany, explained how radioisotopes of CXCR4 can be used for visualizing and treating various cancers. CXCR4, or chemokine receptor type 4, is a G-protein coupled receptor with important roles in lymphocytes and hematopoietic stem cells. In cancer, CXCR4 tends to be upregulated within the tumor. CXCR4-directed therapy is thought to address the stem cell niche and tumor microenvironment. Thus, CXCR4-targeting radioisotopes were used for diagnostic imaging and endoradiotherapy.

CXCR4 PET and CT imaging for cancer visualization

Photograph of medical professional examining imaging results during a patient's radiotheranostics treatment.
PET and CT imaging is used to visualize tumors during radiotheranostics therapy.
ISTOCK, megaflopp

Werner and colleagues used the previously reported CXCR4 radioisotope, 68-Gallium PentixaFor,1 to examine 690 patients with positron emission tomography (PET) and computerized tomography (CT) imaging for myeloma, lymphoma, adrenocortical carcinoma, small-cell lung cancer, and a few other solid cancers. They observed high radiotrace accumulation inside the tumor compared to low background accumulation, thereby making the cancer easy to identify. Notably, 68-Gallium PentixaFor PET/CT enabled visualization of tumor heterogeneity that would otherwise not be detected, and therefore, may not be treated.

CXCR4 radiotherapy for targeted cancer destruction

Once the tumor cells displaying CXCR4 on the cell surface are visualized, CRXC4-linked Lutetium-177/Yttrium-90 PentixaTher can be used for targeted destruction of these cells; different radioisotopes are used than for imaging because these are better emitters of radiation compared to Gallium-68. Prior to therapy, a test run is conducted to measure the radioisotope kinetics in various organs to determine the dose of the radioisotope used for treatment. 

According to Werner, CXCR4-targeted therapy is useful for hematological cancers to simultaneously achieve significant anti-tumor effects and conduct myeloablation. Myeloablation, or severely decreased bone marrow activity, is required prior to hematopoetic stem cell transplantation. Their findings were in line with a few other studies using CXCR4 radiotheranostics in end-stage hematological cancers. While some patients could not be treated or showed only partial remission, as seen with other treatments of these aggressive cancers, remarkably, a few patients showed complete remission.

Werner and colleagues are also currently investigating this treatment option for certain solid cancers. Given that myeloablation would be a serious side effect when transplantation is not intended, CXCR4-targeted therapy could be used for aggressive solid cancers that have limited treatment options and/or are unresponsive to current treatments. Their preliminary data suggests CXCR4 radiotheranostics may help stabilize aggressive solid tumors.

Considerations for radiotheranostics use

A key advantage of radiotheranostics from a clinical perspective is that patients report fewer side effects than other cancer therapies, and when they do, it consists of fatigue and nausea. Although radiotheranostics is a systemic treatment, it is well tolerated in comparison to systemic radiation and chemotherapy. Potential toxic effects ultimately depend on the specific molecule being administered and the dose, and can include nephrotoxicity and myelosuppression.2 Increasingly, radiotheranostics are being delivered with catheters or image-guided intervention, which further ensures clinicians can target cancerous cells to reduce overall side effects.

Thus far, the main goal for radiotheranostics has been to stabilize end-stage disease that does not respond to other treatments, and to improve quality of life for these patients. Moving forward, radiotheranostics treatments are also being designed to treat early-stage cancer, and even non-cancer conditions, such as treating synovitis in knee osteoarthritis.3 

But while researchers continue to be interested in using radiotheranostics for basic, preclinical, and translational research on current and new targets, radiotheranostics still faces crucial changes.4 Perhaps the most formidable of these is the lack of interdisciplinary teams with radiotheranostics expertise. Furthermore, the isotopes used in radiotheranostics have restricted availability, significantly limiting its availability across the world. Lastly, since it is not yet a mainstream therapy, there are concerns around patients and medical professionals being reimbursed by insurance companies. Nonetheless, with a broadening approach in oncology, as well as a focus on precision medicine, radiotheranostics provides a promising avenue for future investigation.


  1. Herrmann K, Schwaiger M, Lewis JS, et al. Radiotheranostics: a roadmap for future development. The Lancet Oncology. 2020;21(3):e146–156.
  2. Wester HJ, Keller U, Schottelius M, et al. Disclosing the CXCR4 expression in lymphoproliferative diseases by targeted molecular imaging. Theranostics. 2015;5(6):618–630.
  3. Bodei L, Kidd M, Paganelli G, et al. Long-term tolerability of PRRT in 807 patients with neuroendocrine tumours: the value and limitations of clinical factors. European Journal of Nuclear Medicine and Molecular Imaging. 2015;42(1):5-19.
  4. Markou P, Chatzopoulos D. Yttrium-90 silicate radiosynovectomy treatment of painful synovitis in knee osteoarthritis. Results after 6 months. Hellenic Journal of Nuclear Medicine. 2009;12(1):33-6.
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Radioisotopes linked to the same ligand used can be used for imaging then treating cancer.