Posted August 15th, 2016 by Luke Ng

Understanding a key roadblock behind nanoparticle cancer drug delivery

U of T researchers Sonya MacParland (right) and Kim Tsoi (IBBME PhD 1T6) are the lead authors on a four-year study that showed how the liver and spleen trapped cancer nanomedicine, preventing them from reaching their intended targets. (Photo: Peter Church)

The emerging field of nanomedicine holds great promise in the battle against cancer. Tiny particles similar in size to protein molecules can be customized to carry tumour-targeting drugs and destroy cancer cells without harming healthy tissue.

But here’s the problem: when nanoparticles are administered into the body, more than 99 per cent of them become trapped in non-targeted organs, such as the liver and spleen. These nanoparticles are not delivered to the site of action to carry out their intended function.

To develop solutions to this problem, researchers at the University of Toronto and the University Health Network figured out how the liver and spleen trap intact nanoparticles as they move through the organ. “If you want to unlock the promise of nanoparticles, you have to understand and solve the problem of the liver,” says Dr. Ian McGilvray, a transplant surgeon at the Toronto General Hospital and scientist at the Toronto General Research Institute (TGRI).

In a study published in the journal Nature Materials, the team discovered that as nanoparticles move through the liver sinusoid, the flow rate slows down 1,000 times, which increases the interaction of the nanoparticles all of types of liver cells. This was a surprising finding because the current thought is that Kupffer cells, responsible for toxin breakdown in the liver, are the ones that gobbles up the particles.  This study found that liver B-cells and liver sinusoidal endothelial cells are also involved and that the cell phenotype also matters.

“We know that the liver is the principle organ controlling what gets absorbed by our bodies and what gets filtered out—it governs our everyday biological functions,” describes Dr. Kim Tsoi, a U of T orthopaedic surgery resident who completed her PhD in biomedical engineering with U of T professor Warren Chan (IBBME), and a first author on the paper. “But nanoparticle drug delivery is a newer approach and we haven’t had a clear picture of how they interact with the liver—until now.”

Tsoi, together with her research partner Sonya MacParland, an immunology post-doctoral fellow at U of T and TGRI, first examined both the speed and location of their engineered nanoparticles as they moved through the liver.

“This gives us a target to focus on,” says MacParland. “Knowing the specific cells to modify will allow us to eventually deliver more of the nanoparticles to their intended target, attacking only the pathogens or tumours, while bypassing healthy cells.”

“Many prior studies that have tried to reduce nanomaterial clearance in the liver have focused on the particle design itself,” says Chan. “But our work now gives greater insight into the biological mechanisms underpinning our experimental observations — now we hope to use our fundamental findings to help design nanoparticles that work with the body, rather than against it.”

With files from Alexandra Radkewycz, University Health Network