When Toronto-based researchers modified nanoparticles with an unexpected compound, in hopes of crossing the impenetrable cancer cell wall, they didn’t anticipate their approach would yield an over 25-fold improvement in cellular uptake, nor that this would occur by fluidizing the cell membrane.
The novel strategy was developed by a team of researchers led by Dr. Gang Zheng, a senior scientist at the Princess Margaret Cancer Centre, and funded by a Terry Fox New Frontiers Program Project Grant.
To achieve these results, the team enlisted the help of a secret weapon: ethylenediaminetetraacetic acid (EDTA). This metal chelator and clinically approved treatment for heavy metal intoxication has been associated with the destabilization of bacterial membranes by chelating metals on their membranes.
By embedding EDTA-hexadecylamide conjugates (EDTA-lipids) into the superstructure of liposomal nanoparticles called porphysomes, which were previously created by Dr. Zheng’s team, they aimed to understand whether EDTA’s metal chelating properties could facilitate porphyrin uptake.
The results were promising in both cell lines and mouse models. “We found that these novel EDTA-lipidbearing porphysomes enhanced porphyrin uptake in cancer cells by over 25-fold,” says Dr. Zheng.
“It was rather unexpected,” he says. “We learned that the uptake mechanism was unrelated to EDTA’s chelation properties. Instead, these EDTA-lipids altered the cell membrane, or ‘fluidized’ it, allowing nanoparticles to pass through.”
Once the nanoparticles are inside the cell and treated with photodynamic therapy (PDT), which involves administering and activating non-toxic photosensitizers within tissues to kill surrounding cells, the team achieved more than 95 per cent cell killing in vitro, compared to less than five per cent of cells killed using porphysomes alone.
"In the near future, this combination can be considered a second-generation porphysome with improvement on its PDT efficacy,” he explains. “Beyond PDT, it could improve the drug delivery of lipid nanoparticles with the hope of improving therapeutic outcomes."
Novel Strategy to Drive the Intracellular Uptake of Lipid Nanoparticles for Photodynamic Therapy
Tiffany Ho, Dr. Keegan Guidolin, Dr. Ali Makky, Michael Valic, Lili Ding, Jiachuan Bu, Mark Zheng, Dr. Miffy H. Y. Cheng, Jeremy Yau, Dr. Juan Chen, Prof. Dr. Gang Zheng
This study was partially funded by a Terry Fox Program Project Grant in Porphysome Nanoparticle-Enabled Image-Guided Cancer Interventions