Targeted Delivery of a Short-Lived Radioactive Compound to Cancer Cells

The power of specific targeting of specific cell types is that any cell-killing mechanism can then be delivered. The more efficient the targeting, more more dangerous and effective the cell-killing mechanism can be. The reason why any given cancer therapy is less effective at killing cancer cells than it might be is because the targeting isn't perfect, and thus there is the need to limit the damage to other tissues in the body.

A cancer-specific L-type amino acid transporter 1 (LAT1) is highly expressed in cancer tissues. Inhibiting the function of LAT1 has been known to have anti-tumor effects, but there has been limited progress in the development of radionuclide therapy agents targeting LAT1. Now, a research team has established a targeted alpha-therapy with a novel drug targeting LAT1.

The researchers first produced the alpha-ray emitter 211-Astatine, no easy task given that Astatine (At) is the rarest naturally occurring element on Earth. Targeted alpha-therapy selectively delivers α-emitters to tumors; the advantage over conventional β-therapy is that alpha decay is highly targeted and the high linear energy transfer causes double-strand breaks to DNA, effectively causing cell death. The short half-life and limited tissue penetration of alpha radiation ensures high therapeutic effects with few side-effects to surrounding normal cells.

Next, to carry the radioisotope into cancer cells, the researchers attached it to α-Methyl-L-tyrosine, which has high affinity for LAT1. This subterfuge exploits the elevated nutrient requirements of rapidly multiplying cancer cells. "We found that 211At-labeled α-methyl-L-tyrosine (211At-AAMT) had high affinity for LAT1, inhibited tumor cells, and caused DNA double-strand breaks in vitro. Extending our research, we assessed the accumulation of 211At-AAMT and the role of LAT1 in an experimental mouse model. Further investigations on a human pancreatic cancer cell line showed that 211At-AAMT selectively accumulated in tumors and suppressed growth. At a higher dose, it even inhibited metastasis in the lung of a metastatic melanoma mouse model."



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