The Paradox of Using Radionuclides To Treat Disease.

Approximately 40% of us will hear at some point in our lives that we have cancer, and nearly 25% of those that hear this grave news will perish from this disease.[1] Paradoxically, while most of us immediately associate radiation with diseases such as cancer, since the Nuclear Age began in the closing years of the 19th Century we have known that radioisotopes and radiation can be used to image, diagnose, and treat disease. Recently, Kozimor and co-workers have discovered a new way for the large-scale isolation and production of 119Sb that may enable targeted radiotherapeutic applications (see Figure ).[2] This radionuclide shows special promise of potentially delivering lethal doses of radiation to targeted diseased cells, reducing side-effects by leaving adjacent healthy tissue unharmed.

Figure 1

Kozimor and co-workers report on a large-scale production method for 119mTe and 119Sb from proton bombardment of Sb target containing natural abundance antimony. X-ray absorption spectroscopy has been used to understand solution speciation to develop improved separation of the 119mTe parent from the 119Sb daughter. The latter will be used in targeted radiotherapy. Reprinted with permission from ref (2). Copyright 2019 American Chemical Society.

As early as 1899, X-rays were applied to successfully treat skin cancer. Shortly thereafter, radium from the Curies’ laboratory found similar uses in the treatment of Lupus and many forms of cancer.[3] Unfortunately, this was rapidly followed by the misuse of radioactive materials for everything from treating virtually every ailment to making glowing clocks, wristwatch faces, and children’s nightlights, and even to intentionally mutating flowering plants to create exotic flowers.[4] Radium became snake oil, and this calamity climaxed with the deaths of the so-called “Radium Girls,” who perished from ingesting large amounts of radium while painting watches.[5] Following these events, nuclear medicine continued under many guises for decades thereafter so as not to be lumped in with mistakes of the past, and many books have been written to describe these events both for technical and general audiences. Notably, in the last 20 years, nuclear medicine has become more societally accepted. This shift in perception is perhaps because enough of general public has come to understand that it can be safely applied to ease, and even cure, what ails us.

In particular, alpha radiotherapy has emerged over the past decade as one of the best methods for treating disease and, in cases when it cannot be cured, to improve quality of life by easing chronic pain.[6] The most significant advantage of alpha therapy is that this radioactive decay mode delivers all of its energy (typically in the MeV range) to only a few layers of cells. Thus, the damage can be localized to the area where it is needed, such as the destruction of a tumor with minimal damage to the surrounding tissue. Perhaps the best-known recent victory in this area is the medication Xofigo, whose production was recently acquired by Bayer because of its broad success.[7] Xofigo relies on obtaining 223Ra from the α-emitter 227Ac, and the subsequent delivery of this radionuclide to diseased areas of bones. The purification of the actinium parent is no small feat and is accomplished by a team at Oak Ridge National Laboratory using robotic hot cell facilities. This treatment can substantially decrease chronic pain caused by metastatic prostate cancer.[7] Many of these patients must make difficult decisions in choosing between unbearable pain or sedation/addictions from opiates. Drugs like Xofigo and Lexidronam, an older medication for treating pain associated with metastatic bone cancer that contains β-emitting 153Sm,[8] offer alternatives to addictive and debilitating pain killers and significantly improve quality of life and end of life care.

Among successful and emerging radiotherapeutics, 119Sb has unique potential in targeted therapeutic applications for low energy electron-emitting isotopes (Auger electrons).[9] These electrons have a biological path length of about 10 μm, which is the width of a single cell. To date, developing 119Sb-based drugs has been slow in comparison to other radionuclides. This is primarily associated with limited access. Typically, 119Sb is prepared in cyclotron facilities in reasonable quantities (0.1–1 Ci). Production routes often involve irradiation of isotopically enriched 119Sn targets. Unfortunately, the relatively short 119Sb half-life (t1/2 = 38.19(22) h) and limited production capabilities present a bottleneck for distribution of usable activity for medical experimentation.

The new 119Sb production and separation method described by Kozimor and co-workers represents an exciting leap forward for targeted radiotherapeutic uses of Auger-emitting isotopes.[2] It offers the opportunity to greatly increase access to 119Sb beyond the relatively limited number of medical institutions that have colocated 119Sb production sites. The team demonstrated that large quantities of 119Sb could be generated by proton irradiation of natural abundance Sb at high energy proton sources, i.e., the Isotope Production Facility (IPF) at the Los Alamos Neutron Science Center (LANSCE) at Los Alamos National Laboratory (LANL) and the Brookhaven Linac Isotope Producer (BLIP) at Brookhaven National Laboratory. The LANL team also developed a purified method that provides large quantities of 119Sb for external use.

One particularly creative aspect of this research campaign is that Kozimor and co-workers adopted an unconventional approach for their radiochemical separation method. They made use of X-ray absorption spectroscopy (XAS) at the Stanford Synchrotron Lightsource (SSRL) to guide efforts to remove Te from Sb. This is apparently the first-time synchrotron spectroscopy has been applied to this area of research. The spectroscopic results were valuable and informed researchers on differences between Te and Sb in aqueous solutions and on solid-state chromatographic supports. The information was used to developed a Te/Sb separation procedure that (1) was compatible with large natSb (25 g) targets, (2) accounted for safety concerns associated with generating large quantities of 119mTe/119Sb, and (3) could be rapidly (∼36 h separation) carried out using remote handling techniques within hot cells.

One of the most interesting discoveries made using this technique is that the Te(IV) was reduced to Te(0) on contact with the column resin. This allowed for more rapid and cleaner separation of the 119Sb daughter from the 119mTe parent than was previously possible because the tellurium gets held up on the top of the column as the result of the reduction. The relatively long lifetime of 119mTe (t1/2 = 4.70(4) days) makes this the likely source of 119Sb that will be transported to hospitals. This is same procedure used for decades to milk 99mTc from 99Mo sources for use as an imaging agent. The potential impact of these results is significant, offering an opportunity to significantly expand efforts to use 119Sb in targeted Auger therapies to treat disease.