Effective internalization of lipid nanoparticles for photodynamic cancer therapy
In order to deliver cancer therapeutics to tumor cells, the cells’
membranes must be overcome. A team of researchers have discovered a
simple way to achieve this using lipid nanoparticles containing the
reagent EDTA (ethylenediaminetetraacetic acid). As the team report in
the journal Angewandte Chemie, an unusual mechanism of action of EDTA is responsible for this useful effect.
© Wiley-VCH, re-use with credit to 'Angewandte Chemie' and a link to the original article.
One of the greatest challenges in cancer therapy is the targeted
delivery of drugs, contained in nanoparticles, to tumor cells, where
they can then kill the cells. Unfortunately, cell membranes are highly
selective in terms of what they allow to pass. Receptors on the membrane
surface usually act as gatekeepers, but devising the precise molecular
key to unlock them is tricky. Liposomes offer one alternative: these
nanoscale lipid spheres simply fuse with the cell membrane, transporting
their therapeutic payloads into the cell in the process. However, more
efficient intracellular uptake is still sought to increase drug
efficacy.
Gang Zheng and colleagues at the Princess Margaret Cancer Centre and
the University of Toronto, Canada, took a closer look at EDTA as a new
way to gain entry to cancer cells. EDTA can chelate metal ions, in other
words securely bind them and remove them from their environment. In
biomedicine, EDTA is used to treat heavy metal poisoning, and it is used
as a contrast agent for bioimaging.
Zheng and the team hypothesized that the chelating effect might be
useful as a cell opener too. As Zheng explains: "A high concentration of
EDTA is known to permeabilize bacterial membranes by chelating metals
(e.g., calcium ions) on their membranes. We wondered whether
incorporating an EDTA-lipid conjugate into liposomes could enhance their
intracellular uptake at a much lower EDTA concentration that is
non-toxic to human cells."
The team therefore incorporated an EDTA-lipid compound into
drug-loaded liposomes, in order to deliver them into tumor cells. The
experimental results even exceeded their expectations, showing
drastically improved internalization in both cell lines and in a mouse
model. In tumor-infected mice, the drug—porphyrins used for photodynamic
therapy—caused the tumor to decline and improved the surviving rates of
the mice significantly.
However, to the team’s great surprise, the chelate effect had nothing
to do with the enhanced internalization. "This process is totally
independent of its metal chelation properties," says Zheng of the team’s
findings. Instead, the group discovered that EDTA acted like a
detergent to change the characteristics of the cell membrane, making it
more fluid and flexible to promote nanoparticle uptake. The group now
plan to apply this newly discovered mechanism to a general
EDTA-lipid-based strategy for cells to absorb liposomal nanoparticles
for enhanced therapy.
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About the Author
Gang Zheng, PhD, is
an Associate Research Director at the Princess Margaret Cancer Centre,
and a Professor at the University of Toronto. The Zheng lab develops new
platform technologies to more effectively diagnose and treat cancer.
They focus on molecular imaging and phototherapy agents as well as the
development of nature-inspired theranostic nanomedicines and clinically
translatable technologies.
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