Therapeutic radioisotopes can be designed to home in on cancer cells, precisely delivering radiation while leaving healthy surrounding cells unscathed. In this Innovation Spotlight, John Babich, the co-founder, president, and chief scientific officer of Ratio Therapeutics, discusses how radiopharmaceuticals are constructed for optimal cancer targeting and treatment.
John Babich
Co-founder, President, and Chief Scientific Officer
Ratio Therapeutics
What are radiopharmaceuticals and what role do they play in cancer treatment?
Radiopharmaceuticals are drugs that combine radioactive isotopes with molecules that target specific cells, such as cancer cells. In cancer treatment, they deliver targeted radiation directly to tumors, minimizing damage to healthy tissues. This precision improves therapy effectiveness, especially for cancers that are difficult to treat with conventional methods. Radiopharmaceuticals can be used to diagnose and treat cancer, offering a dual approach that improves accuracy in detecting tumors and provides a powerful tool to destroy them, especially for metastatic or late-stage disease.
How are radiopharmaceuticals different from other cancer therapeutics? What challenges do radiopharmaceuticals try to solve?
Many traditional cancer therapies, such as chemotherapy, are limited because they indiscriminately attack both healthy and cancerous cells, leading to significant side effects. External beam radiotherapy is effective for localized disease. Therapeutic radiopharmaceuticals are administered systemically and therefore can deliver radiation to cancers spread throughout the body. The precise targeting of radiopharmaceuticals to cancer cells minimizes off-target localization in normal tissues, thereby minimizing adverse effects on these tissues. This precision targeting lowers toxicity and enhances effectiveness, especially for widespread metastatic tumors. Additionally, radiopharmaceuticals help researchers visualize and treat cancer, depending on the radioisotope used to prepare the radiopharmaceutical. This enables a more tailored solution for patients resistant to conventional therapies.
Can you provide an example of how a radiopharmaceutical works?
A radiopharmaceutical functions like a locksmith using a specialized key to unlock a specific door. The cancer cells are like locked doors, and traditional therapies are akin to using a crowbar, which can open any door but damages the doorframe and surrounding area. Radiopharmaceuticals, however, are tailored keys designed to fit only the locks of cancer cells. The interaction with the specific receptors on these cells allows selective delivery of targeted radiation, effectively opening the door to treatment while preserving the integrity of the healthy cells nearby. This precision enhances the effectiveness of cancer therapy and minimizes collateral damage.
How do scientists keep a radiopharmaceutical stabilized until it reaches its destination?
Scientists can design optimized radiopharmaceuticals to enhance their circulation throughout the body and improve tumor delivery.
The typical components in a radiopharmaceutical critical for its ability to successfully reach its target are the targeting moiety, a linker, a chelator, and a radioisotope. Ideally, a radioactive isotope is paired with a suitable chelator—usually a metal—that securely binds to it. The chelator is chemically attached to the targeting moiety through a linker. This compound structure of ligand, linker, chelator, and isotope ensures that the radiopharmaceutical stays intact in order to successfully reach its target on the cancer cell. In addition, the radiopharmaceutical is prepared in a formulation matrix that maintains chemical stability during manufacturing and shipping.
How do scientists choose which radioisotope to use, and what are some of the benefits of alpha-emission versus beta?
The choice of radioisotope depends on the therapeutic need, including the type of cancer and the treatment goal. Scientists evaluate factors such as the isotope’s half-life, radiation type, delivered radiation energy potential, and range. Alpha-emitting isotopes deliver high-energy radiation over a very short distance, making them ideal for targeting small, localized tumors with minimal effects on surrounding healthy tissue. In contrast, beta-emitting isotopes release lower-energy radiation over a longer range, making them more suitable for treating larger or more diffuse tumors. Each isotope type offers unique benefits tailored to the specific characteristics of the cancer being treated.
How can the design of structural motifs be tuned to optimize for target type, location, and delivery needs?
The design of structural motifs for radiopharmaceuticals can be optimized by focusing on target affinity, pharmacokinetics, and delivery efficiency. With this in mind, we have designed a platform, named Trillium, which enables radiotherapeutics to bind to albumin, thereby enhancing circulation throughout the body and improving tumor delivery. By tailoring reversible binding to albumin, we adjust the plasma retention curve, ensuring the radiopharmaceutical remains in circulation longer for more precise tumor targeting.
How could radiopharmaceuticals combine with other cancer therapies?
When combined with immunotherapies, radiopharmaceuticals deliver radiation directly to tumors, damaging cancer cells and increasing their visibility to the immune system. This makes the cancer more susceptible to immune attack, boosting the effectiveness of treatments such as immune checkpoint inhibitors. Additionally, debris from damaged cells can create an inflammatory environment that enhances immune response, helping immunotherapies penetrate and act on the tumor more effectively. This combination offers a synergistic approach, maximizing the strengths of both treatments for better cancer control.
What about the future of radiopharmaceuticals excites you the most?
From a technological perspective, radiotherapeutics have the potential to become an integral part of cancer treatment, particularly as an adjuvant. We are likely to see advancements in the use of radiotherapeutics before surgery or immunotherapy to enhance treatment outcomes. This includes translating preclinical research into clinical practice, where targeted radiopharmaceuticals could play a key role in managing disease. The ability to combine this technology with other approaches will offer new, personalized ways to treat cancer, ultimately improving patient care and outcomes.
