Researchers at the University of Toronto have developed an alternative theory to explain how nanoparticles enter and exit the tumours they are meant to treat. This new principle debunks a leading theory in cancer nanomedicine that has guided research for nearly four decades.
The Enhanced Permeability and Retention (EPR) effect, a concept largely unchallenged since the mid-1980s, posits that nanoparticles enter a tumour from the bloodstream through gaps between the endothelial cells that line its blood vessels, then become trapped in the tumour due to dysfunctional lymphatic vessels.
“The retention aspect of the EPR theory is contingent on the lymphatic vessel cavity being too small for nanoparticles to exit, thereby helping nanoparticles that carry cancer-fighting drugs to stay in the tumours,” said Matthew Nguyen, a PhD student at the Institute of Biomedical Engineering and the Donnelly Centre for Cellular and Biomolecular Research, and lead author on a new study that challenges the long-standing theory.
“But we found around 45 per cent of nanoparticles that accumulate in tumours will end up exiting them,” said Nguyen, a member of the lab of Warren Chan, professor of nanobioengineering at U of T (cross-appointmented with the Department of Chemistry).
The findings help explain why treatments based on the EPR effect are failing in clinical trials, and build on earlier research from the Chan lab that showed less than one per cent of nanoparticles actually reach tumours.
The journal Nature Materials published the results recently.
The researchers found that, contrary to the EPR effect, nanoparticles can leave tumours through their lymphatic vessels. The exit method for a nanoparticle depends on its size, with larger ones (50-100 nm wide) more likely to leave through lymphatic vessels in the tumours, and smaller ones (up to 15 nm wide) more likely to leave through lymphatic vessels surrounding the tumours.
In rare cases, nanoparticles will exit through blood vessels.
Nanoparticle exit from tumours occurs through spaces in the lymphatic vessel walls and transport vesicles that carry them across these walls. The researchers showed that nanoparticles will re-enter the bloodstream following lymphatic drainage, and hypothesized that these nanoparticles will eventually return to the tumour for another opportunity to treat it.
Disproving the EPR effect was no easy feat: the Chan lab spent six years working to understand why nanoparticles do not accumulate in tumours effectively. Prior to this study, the lab focused on how nanoparticles enter tumours in the first place. Through this and other studies, the lab developed a competing theory to the EPR effect, called the Active Transport and Retention (ATR) principle.
Nguyen noted that the field of nanomedicine has evolved since the publication of the nanoparticle entry study in 2020. “We got more pushback from other researchers on that study compared to this one,” he said. “People have started to accept that the EPR effect is flawed.”
With nearly half of accumulated nanoparticles exiting tumours, mostly through lymphatic vessels, future research could address this issue through nanoparticle treatments that prevent lymphatic drainage.
“We are excited to have a better understanding of the nanoparticle tumour delivery process,” said Chan. “The results of these fundamental studies on nanoparticle entry and exit will be important for engineering nanoparticles to treat cancer.”
The findings of this study, if applied across the field of cancer nanomedicine, promise a new direction to improve our understanding of how nanoparticles can be used to treat tumours.
“Trying to translate cancer nanomedicine to the clinic is like a working with a black box — some drugs work, some don’t, and it’s difficult to know why,” said Gang Zheng, a professor of medical biophysics at U of T’s Temerty Faculty of Medicine and associate research director at the Princess Margaret Cancer Centre, who was not involved in the study.
“Chan’s dedication to better understanding the mechanisms of nanoparticle uptake and exit is shining light on these processes to help make our translation efforts more efficient and successful,” Zheng said.
This research was supported by the Canadian Cancer Society, the Canadian Institute of Health Research, NanoMedicines Innovation Network and the Canadian Research Chairs Program.