On a chilly morning at the end of January 1896, Ms. Rose Lee found herself at the forefront of a groundbreaking medical practice at a lightbulb factory in Chicago. Little did she know, a doctor was placing an X-ray tube over a tumor in her left breast, using a stream of high-energy particles to penetrate the malignant growth. This moment marked the birth of X-ray therapy.

Since that time, radiation therapy has witnessed significant advancements. With the discovery of radium and other radioactive elements, the medical field has been able to deliver higher doses of radiation to tumors located deep within the body. The introduction of proton therapy further improved the precision of radiation treatments. Advances in medical physics, computer technology, and imaging techniques have greatly enhanced the accuracy of these therapies.

However, it wasn’t until the year 2000 with the advent of targeted radiopharmaceuticals—also known as “nuclear medicine”—that radiation therapy achieved molecular-level precision. These drugs are highly specific and can track cancer like a guided missile, delivering radioactive substances directly to tumors through the bloodstream. They not only play a crucial role in the accurate diagnosis and treatment of serious illnesses but also contribute valuable information for clinical decision-making due to their unique in vivo imaging capabilities.

Currently, only a handful of targeted radiopharmaceuticals are available for clinical use. Nevertheless, with leading biopharmaceutical companies increasing their investments in this field, we can expect more such drugs to emerge in the future, offering new hope for patients.

Despite some setbacks in clinical applications, research continues. Today, there is considerable interest in radiopharmaceuticals. However, broadening the use of this therapy to encompass more types of cancer will require the development of new tumor-targeting particles and the identification of additional suitable targets.

For decades, radioactive iodine has been widely utilized because of its ability to be absorbed by the thyroid and destroy cancer cells, yet it has primarily been effective for thyroid cancer. Other cancers do not exhibit similar affinities for radioactive elements, prompting researchers to create drugs that identify and attach to specific proteins on tumor cells, serving as targeted carriers to deliver radioactive isotopes directly into the affected areas.

Nonetheless, it has been challenging for treatments combining radioactive isotopes with targeted molecules to establish a foothold in standard cancer therapies. Quadramet, approved in 1997 for alleviating cancer-related bone pain rather than shrinking tumors, saw limited clinical use. In the early 2000s, two new drugs aimed at lymphoma showed promising results in clinical trials, but failed to compete with non-radioactive treatments and were subsequently dropped.

These setbacks led to a stagnation in investment in radiopharmaceuticals. Still, research has persisted, as demonstrated by the radioactive-labeled antibody trials for prostate cancer that Weill Cornell Medical College has been conducting since 2000. These efforts are laying the groundwork for a potential resurgence of radiopharmaceuticals.

Hope has been reignited with the introduction of lutetium-based drugs. In Europe, clinicians have made strides in developing radioactive-labeled therapies targeting somatostatin receptors. After testing various radioactive payloads, researchers ultimately concentrated on lutetium isotopes, which are favored due to their lower toxicity to the kidneys and longer half-life.

Simultaneously, Lutathera, a lutetium-labeled drug developed by the French company AAA, has significantly slowed the progression of gastrointestinal tumors and received swift approval in Europe and the U.S. Shortly after, Endocyte, a company acquired by Novartis, developed Pluvicto, a drug targeting prostate-specific membrane antigen (PSMA), which has extended the time to disease progression and survival in advanced prostate cancer patients.

Both Pluvicto and Lutathera are based on specific peptides designed to bind to targeted receptors on cancer cells. In prostate cancer treatment, Pluvicto targets the PSMA receptor, while Lutathera focuses on somatostatin receptors. These drugs are administered via infusion, circulating through the bloodstream until they encounter and firmly attach to tumor cell surfaces.

Once anchored at the target site, the lutetium isotopes release beta particles and gamma rays to disrupt DNA and induce cancer cell death. Additionally, gamma rays allow healthcare providers to track the drug’s distribution within the body in real time.

Current research trends and substantial industry investments are increasingly shifting towards therapies that leverage alpha isotopes. Compared to beta particles, alpha particles have greater mass and higher energy, capable of tearing apart DNA and causing highly localized cellular destruction. This effect is often likened to “detonating a shell within the cell.”

Moreover, alpha particles have a relatively short range, typically limited to several tens of micrometers, in stark contrast to beta particles that can penetrate several millimeters of tissue. Consequently, therapies utilizing alpha particles offer a highly localized effect, systematically destroying tumor tissue while minimizing damage to surrounding healthy cells.

Next-generation alpha particle radiopharmaceuticals may target PSMA in prostate cancer. Developers aim to surpass Pluvicto and incorporate additional functions to enhance efficacy. For instance, U.S.-based Convergent is developing an alpha particle drug that has a long retention time and lower salivary gland toxicity.

In the competitive quest for the next groundbreaking target, Novartis has emerged as a leader. The company is working on a new generation of radiolabeled drugs and expanding production capabilities. Earlier this year, Novartis opened a $100 million dedicated production facility in Indianapolis, with plans to produce hundreds to thousands of doses daily. This marks a stark contrast to the rudimentary setup at the Chicago lightbulb factory more than a century ago.