By David N. Leff

It took 35 years to happen, but the award-winning 1966 movie, Fantastic Voyage, starring Raquel Welch, has finally come true. You may remember this sci-fi film, in which a team of surgeons and physicians are shrunk to microscopic size, and injected into the blood vessels and organs of a trauma patient, to repair his injuries.

Now a team of oncologists and chemists at the Memorial Sloan-Kettering Cancer Center (MSKCC) in New York has injected a radioactive atom, hooked onto a tumor-seeking monoclonal antibody, into mice ¿ and cured their prostate cancer.

Today¿s Science, dated Nov. 16, 2001, reports their feat in a paper titled: ¿Tumor therapy with targeted atomic nanogenerators.¿ Its senior author is clinical oncologist David Scheinberg, who heads MSKCC¿s Laboratory of Hematopoietic Cancer Immunochemistry. The article¿s lead author is chemist Michael McDevitt, a senior scientist in Scheinberg¿s lab.

Their weapon for killing tumor cells is a single atom of the radioactive metal, actinium-225. Actinium doesn¿t occur in nature; it¿s a breakdown product of uranium and thorium. Once an atom of actinium enters its target cell, it spews out a cascade of high-energy alpha particles, which destroy the cell.

To zero in on its target, the co-authors designed a molecule-sized ¿cage¿ containing the actinium nose-cone coupled to a specific cell-seeking monoclonal antibody. ¿Initially,¿ McDevitt recounted to BioWorld Today, ¿we constructed a device about the size of a ballpoint pen ¿ 1 cm by 6 cm by 0.5 cm ¿ with actinium-225 loaded on that column. We eluted it and got bismuth-213 ¿ a decay isotope of actinium-225. The isotope that was eluted off it was placed on an antibody to be used for clinical trials. We then transcended from macroscale generators that produced alpha particle isotopes to reduce the dimensions to the present nano-proportion single-molecule size.¿

A Molecule-Size Baseball Glove

To create this hyper-miniaturized payload, Scheinberg enlisted the Dow Chemical Co., of Freeport, Texas, specialists in metal chelating. One of these Dow scientists, R. Keith Frank, a co-author of the Science paper, explained to BioWorld Today:

¿A chelating agent is an organic molecule,¿ he began, ¿that will wrap around a metal ion and control its destiny. You can think of the tumor-killing construct as a molecular cage. We refer to it as a bifunctional chelating agent. On one side of the molecule you have the actinium-chelating and on the other end the reactive group that attaches to the antibody. The cage effect comes in because the metal fits on the inside and this construct wraps around it, and holds it tightly, like a catcher¿s mitt grabbing the ball.

¿Actinium is an alpha emitter,¿ Frank continued. ¿An alpha particle is essentially a helium nucleus, which obviously is a lot bigger than an electron. But it packs quite a wallop. It doesn¿t travel very far ¿ only a few cell diameters. But an alpha has a very high linear energy transfer. So it delivers a lot of power in the short path it traverses. The upshot is that it¿s very toxic to the target cell because it delivers so much energy.

¿People are starting to look at alpha emitters for use in therapy,¿ Frank went on, ¿but they face some problems. Three of the alpha emitters under current study have very short half-lives ¿ 45 minutes, 60 minutes and 7 hours. Actinium is attractive because it has a 10-day half-life. That makes manufacture of a therapeutic product a little more reasonable.

¿It¿s also got another feature,¿ Frank pointed out, ¿that¿s nice, but can be problematic. That is, its radioactivity decays into three other radioactive daughter atoms, which are also alpha emitters. For each actinium atom-225 that decays you get four new alpha particles. So the deal with actinium is it doesn¿t give you one, or two, but four high-energy alpha particles.¿

Or in Scheinberg¿s words: ¿When actinium decays, it produces a series of three daughter atoms, each of which gives off its own cancer cell-blasting alpha particle. So actinium gives you four times the punch from one atom.¿

He and his team tested this generator bomb in nude mice bearing implanted solid prostate carcimoma tumors. By 10 or 12 days after implantation, each burgeoning cancer had thousands of tumor cells. On day 12 the team inoculated them with the actinium/antibody generator. These mice on average survived 158 days, compared to only 63 days for animals treated on day 15, after the tumors had gone on growing. Many of them had their prostate-specific antigen (PSA) levels decreased to zero, or reduced. (PSA is a common measure of prostate cancer in humans.) They had no evidence of prostate tumor at the time of death on day 293.

The MSKCC investigators also exposed a gamut of cancer cell types in vitro to their nanogenerator. Leukemia, lymphoma, breast, ovarian and neuroblastoma all succumbed to the generator at extremely low-dosage concentrations.

Keeping Daughter Atoms In Line

¿Targeting the generator to the inside of the cancer cells increases the treatment¿s effectiveness,¿ McDevitt pointed out. ¿If the atom is sitting on the cell¿s exterior,¿ he explained, ¿the alpha particle can travel in any direction, so it kills the cells only a fraction of the time. In addition, keeping the generator inside the cell greatly reduces the possibility that the daughter atoms could float off and damage healthy cells.¿

¿Actinium¿s 10-day half-life,¿ Scheinberg noted, ¿allows physicians time to administer the drug after it has been manufactured, and secure a supply of it from the Department of Energy because it¿s a waste product from nuclear power plants and weapons facilities.¿

He and his team plan to file an IND application with the FDA to begin human trials next year. Although the mice treated with the generator seemed to experience no toxic side effects, he observed, ¿the true test of whether this will become an effective therapy won¿t be known until those human trials begin.¿

Commenting on the Science paper, Dow¿s Frank observed: ¿I think this is an important article because people have not in the past taken actinium-225 seriously as a therapeutic owing to its high-power, radioactive, alpha-emitting daughter atoms. In the past,¿ he concluded, ¿people have had trouble chelating actinium, and this is where the Dow chelating ligand comes in.¿