Dentro de un tubo de vidrio estrecho se encuentra una sustancia que puede dañar o curar, dependiendo de cómo lo uses. Emite un tenue resplandor azul, un signo de su radiactividad. Si bien la energía y las partículas subatómicas que emite pueden dañar las células humanas, también pueden matar algunos de nuestros cánceres más rebeldes. Esta sustancia es actinio-225.

Afortunadamente, Los científicos han descubierto cómo aprovechar el poder del actinio-225 para siempre. Pueden adherirlo a moléculas que pueden ubicarse solo en las células cancerosas. En ensayos clínicos que tratan a pacientes con cáncer de próstata en estadio avanzado, el actinio-225 acabó con el cáncer en tres tratamientos.

"No hay un impacto residual del cáncer de próstata. Es notable, "dijo Kevin John, investigador del Laboratorio Nacional de Los Alamos (LANL) del Departamento de Energía (DOE). El actinio-225 y los tratamientos derivados de él también se han utilizado en los primeros ensayos para la leucemia. melanoma, y glioma.

Pero algo se interpuso en el camino de la expansión de este tratamiento.

Por décadas, un lugar en el mundo ha producido la mayor parte del actinio-225:el Laboratorio Nacional Oak Ridge del DOE (ORNL). Incluso con otras dos instalaciones internacionales que contribuyen con cantidades más pequeñas, los tres combinados solo pueden crear suficiente actinio-225 para tratar a menos de 100 pacientes al año. Eso no es suficiente para realizar nada más que los ensayos clínicos más preliminares.

Para cumplir con su misión de producir isótopos que escasean, El Programa de Isótopos de la Oficina de Ciencias del DOE está liderando los esfuerzos para encontrar nuevas formas de producir actinio-225. A través del esfuerzo de investigación Tri-Lab del programa de isótopos del DOE para proporcionar 225Ac producido por aceleradores para el proyecto de radioterapia, ORNL, LANL, y el Laboratorio Nacional Brookhaven (BNL) del DOE han desarrollado un nuevo proceso extremadamente prometedor para producir este isótopo.

Construyendo sobre un legado de la era atómica

La producción de isótopos para la investigación médica y de otro tipo no es nada nuevo para el DOE. Los orígenes del Programa de Isótopos se remontan a 1946, como parte del esfuerzo del presidente Truman para desarrollar aplicaciones pacíficas de la energía atómica. Desde entonces, la Comisión de Energía Atómica (predecesora del DOE) y el DOE han estado fabricando isótopos para usos industriales y de investigación. Los desafíos únicos que conlleva la producción de isótopos hacen que DOE sea ideal para esta tarea.

Los isótopos son diferentes formas de los elementos atómicos estándar. Si bien todas las formas de un elemento tienen el mismo número de protones, los isótopos varían en su número de neutrones. Algunos isótopos son estables, pero la mayoría no lo son. Los isótopos inestables se descomponen constantemente, emitiendo partículas subatómicas como radiactividad. A medida que liberan partículas, los isótopos se transforman en diferentes isótopos o incluso en diferentes elementos. La complejidad de producir y manipular estos isótopos radiactivos requiere experiencia y equipo especializado.

El programa de isótopos del DOE se centra en la fabricación y distribución de isótopos que escasean y tienen una gran demanda, mantener la infraestructura para hacerlo, y realizar investigaciones para producir isótopos. Fabrica isótopos que las empresas privadas no comercializan.

Un luchador excepcional contra el cáncer

La producción de actinio-225 lleva la experiencia de los laboratorios nacionales a un nuevo ámbito.

El actinio-225 es muy prometedor porque es un emisor alfa. Los emisores alfa descargan partículas alfa, que son dos protones y dos neutrones unidos. Como las partículas alfa dejan un átomo, depositan energía a lo largo de su corto camino. Esta energía es tan alta que puede romper enlaces en el ADN. Este daño puede destruir la capacidad de las células cancerosas para repararse y multiplicarse, incluso matando tumores.

"Los emisores alfa pueden funcionar en casos en los que nada más funciona, "dijo Ekaterina (Kate) Dadachova, investigador de la Facultad de Farmacia y Nutrición de la Universidad de Saskatchewan que probó el actinio-225 producido por el DOE.

Sin embargo, sin una forma de atacar las células cancerosas, Los emisores alfa serían igualmente dañinos para las células sanas. Los científicos unen emisores alfa a una proteína o anticuerpo que coincide exactamente con los receptores de las células cancerosas. como colocar una cerradura en una llave. Como resultado, el emisor alfa solo se acumula en las células cancerosas, donde emite sus partículas destructivas a una distancia muy corta.

"Si la molécula está diseñada correctamente y va al objetivo en sí, matas solo las células que están alrededor de la célula objetivo. No matas las células que están sanas, "dijo Saed Mirzadeh, un investigador de ORNL que comenzó el esfuerzo inicial para producir actinio-225 en ORNL.

El actinio-225 es único entre los emisores alfa porque solo tiene una vida media de 10 días. (La vida media de un isótopo es la cantidad de tiempo que tarda en descomponerse a la mitad de su cantidad original). En menos de dos semanas, half of its atoms have turned into different isotopes. Neither too long nor too short, 10 days is just right for some cancer treatments. The relatively short half-life limits how much it accumulates in people's bodies. Al mismo tiempo, it gives doctors enough time to prepare, administer, and wait for the drug to reach the cancer cells in patients' bodies before it acts.

Repurposing Isotopes for Medicine

While it took decades for medical researchers to figure out the chemistry of targeting cancer with actinium-225, the supply itself now holds research back. En 2013, the federal Food and Drug Administration (FDA) approved the first drug based on alpha emitters. If the FDA approves multiple drugs based on actinium-225 and its daughter isotope, bismuth-213, demand for actinium-225 could rise to more than 50, 000 millicuries (mCi, a unit of measurement for radioactive isotopes) a year. The current process can only create two to four percent of that amount annually.

"Having a short supply means that much less science gets done, " said David Scheinberg, a Sloan Kettering Institute researcher who is also an inventor of technology related to the use of actinium-225. (This technology has been licensed by the Sloan Kettering Institute at the Memorial Sloan Kettering Cancer Center to Actinium Pharmaceuticals, for which Scheinberg is a consultant.)

Part of this scarcity is because actinium is remarkably rare. Actinium-225 does not occur naturally at all.

Scientists only know about actinium-225's exceptional properties because of a quirk of history. En los años 1960, scientists at the DOE's Hanford Site produced uranium-233 as a fuel for nuclear weapons and reactors. They shipped some of the uranium-233 production targets to ORNL for processing. Those targets also contained thorium-229, which decays into actinium-225. En 1994, a team from ORNL led by Mirzadeh started extracting thorium-229 from the target material. They eventually established a thorium "cow, " from which they could regularly "milk" actinium-225. In August 1997, they made their first shipment of actinium-225 to the National Cancer Institute.

En la actualidad, scientists at ORNL "milk" the thorium-229 cow six to eight times a year. They use a technique that separates out ions based on their charges. Desafortunadamente, the small amount of thorium-229 limits how much actinium-225 scientists can produce.

Accelerating Actinium-225 Research

Por último, the Tri-Lab project team needed to look beyond ORNL's radioactive cow to produce more of this luminous substance.

"The route that looked the most promising was using high-energy accelerators to irradiate natural thorium, " said Cathy Cutler, the director of BNL's medical isotope research and production program.

Only a few accelerators in the country create high enough energy proton beams to generate actinium-225. BNL's Linear Accelerator and LANL's Neutron Science Center are two of them. While both mainly focus on other nuclear research, they create plenty of excess protons for producing isotopes.

The new actinium-225 production process starts with a target made of thorium that's the size of a hockey puck. Scientists place the target in the path of their beam, which shoots protons at about 40 percent the speed of light. As the protons from the beam hit thorium nuclei, they raise the energy of the protons and neutrons in the nuclei. The protons and neutrons that gain enough kinetic energy escape the thorium atom. Además, some of the excited nuclei split in half. The process of expelling protons and neutrons as well as splitting transforms the thorium atoms into hundreds of different isotopes – of which actinium-225 is one.

After 10 days of proton bombardment, scientists remove the target. They let the target rest so that the short-lived radioisotopes can decay, reducing radioactivity. They then remove it from its initial packaging, analyze it, and repackage it for shipping.

Then it's off to ORNL. Scientists there receive the targets in special containers and transfer them to a "hot cell" that allows them to work with highly radioactive materials. They separate actinium-225 from the other materials using a similar technique to the one they use to produce "milk" from their thorium cow. They determine which isotopes are in the final product by measuring the isotopes' radioactivity and masses.

Trials and Tribulations

Figuring out this new process was far from easy.

Primero, the team had to ensure the target would hold up under the barrage of protons. The beams are so strong they can melt thorium – which has a melting point above 3, 000 degrees F. Scientists also wanted to make it as easy as possible to separate the actinium-225 from the target later on.

"There's a lot of work that goes into designing that target. It's really not a simple task at all, " said Cutler.

Próximo, the Tri-Lab team needed to set the beamlines to the right parameters. The amount of energy in the beam determines which isotopes it produces. By modeling the process and then conducting trial-and-error tests, they determined settings that would produce as much actinium-225 as possible.

But only time and testing could resolve the biggest challenge. While sorting actinium out from the soup of other isotopes was difficult, the ORNL team could do it using fairly standard chemical practices. What they can't do is separate out the actinium-225 from its longer-lived counterpart actinium-227. When the team ships the final product to customers, it has about 0.3 percent actinium-227. With a half-life of years rather than days, it could potentially remain in patients' bodies and cause damage for far longer than actinium-225 does.

To understand the consequences of the actinium-227 contamination, the Tri-Lab team collaborated with medical researchers, including Dadachova, to test the final product. After analyzing the material for purity and testing it on mice, the researchers found no significant differences between the actinium-225 produced using the ORNL and the accelerator method. The amount of actinium-227 was so miniscule that it "doesn't make any difference, " said Dadachova.

Happily Ever After?

Having resolved many of the biggest issues, the Tri-Lab project team is in the midst of working out the new process's details. They estimate they can provide more than 20 times as much actinium-225 to medical researchers as they were able to originally. Those researchers are now investigating what dosages would maximize effectiveness while minimizing the drug's toxicity. Al mismo tiempo, the national labs are pursuing upgrades to expand production to the level needed for a commercial drug. They're also working to make the entire process more efficient.

"Having a larger supply from the DOE is essential to expanding the trials to more and more centers, " said Scheinberg. With the Tri-Lab project ahead of schedule, it appears that the new production process for actinium-225 could lead to a better ending for more patients than ever before.