Doubt cast on mechanism of cancer nanomedicine

The challenge of chemotherapy—indeed, of any cancer treatment—is to kill off tumor cells without doing too much harm to healthy ones. Nanotechnology promised a solution: The blood vessels that grow inside solid tumors are irregular and riddled with gaps between their cells. Nanoparticles up to 300 nm in diameter can fit through those gaps. So nanoparticles loaded with a chemotherapy drug should, it stands to reason, selectively enter and attack the tumor but leave the healthy tissue alone.

Two and a half decades of nanomedicine research have yielded a few nanoparticle drug formulations that outperform their molecular counterparts. (See the article by Jennifer Grossman and Scott McNeil, Physics Today, August 2012, page 38 .) The mechanism of their action, however, has never been fully verified. No technique exists to image nanoparticles, in vivo and in real time, with sufficient resolution to observe the particles slipping through the intercellular gaps in the tumor’s blood vessels.

New research by Shrey Sindhwani , Abdullah Muhammad Syed (both with Warren Chan’s laboratory at the University of Toronto), and their colleagues suggests that most nanoparticles that end up in tumors don’t get there through the blood-vessel gaps. Rather, they found that between 75% and 97%, depending on the nanoparticle size and type, enter the tumor via an active transcellular pathway. For example, individual cells in the blood-vessel walls might engulf the nanoparticles and expel them into the surrounding tumor.

To reach that conclusion, the researchers used a combination of imaging techniques, experiments, and simulations. In one of their experiments, they developed model mice they called Zombies: tumor-bearing mice that are not only dead but chemically treated to halt all cellular activity. They pumped nanoparticle-infused blood through the vessels of Zombie mice and injected the same nanoparticles into control, or live, mice. If nanoparticles enter tumors by passively flowing through intercellular gaps, then equal numbers of nanoparticles should be delivered to the tumors of control and Zombie animals.

But that’s not what happened. Fluorescence images in the figure show tumor blood vessels in red and nanoparticles in green; nanoparticles in the control mouse appear throughout the tumor, but in the Zombie mouse they remain confined to the blood vessels. In other words, nanoparticles escape the tumor blood vessels only when the cells in the vessel walls are alive.

Although the biological details of the putative mechanism remain to be worked out, the result has important consequences for future nanomedicine research: An active biological transport pathway is sensitive to nanoparticle surface chemistry and composition in ways that a passive physical mechanism isn’t. (S. Sindhwani et al., Nat. Mater., 2020, doi:10.1038/s41563-019-0566-2 .)