For cancer drug developers, finding an agent that kills tumor cells is only
part of the equation. The drug must also spare healthy cells, and - ideally
- its effects will be reversible, to cut short any potentially dangerous side
University of Illinois researchers
report that they have assembled a new cancer drug delivery system that, in cell
culture, achieves all of the above. The findings appear this month in the journal
The team began with the knowledge that small, membrane-bound compartments,
called liposomes, are useful as drug-delivery vehicles. When linked to molecules
that target receptors on cancer cells, liposomes can enter and dump their cancer-killing
contents into those cells.
Scientists have spent more than a decade trying to direct liposomes to specific
cancer cells, with limited success. A common approach involves attaching an
antibody to the liposome membrane. Ideally the antibody will bind to a cancer
cell receptor so that it can deliver the liposome – and the cancer drug
– into the cell.
Developing such antibodies is costly and time-consuming, however, and the process
of attaching them to liposomes is difficult to control. Antibodies spur an immune
response, requiring extra steps to create a useable therapeutic agent, and the
ability of antibody-conjugated liposomes to bind to cancer cells can be inconsistent.
Some small molecules, such folate, a vitamin, also work as cancer cell targeting
agents, but those now in use are not as good as antibodies at binding to cancer
To solve the cell-targeting problem, the U. of I. team turned its attention
to small molecules called aptamers.
"Aptamers are short strands of DNA or RNA; they are highly efficient binders,
and are very easy to make, label and manipulate," said Zehui Cao, a postdoctoral
researcher in the laboratory of chemistry professor Yi Lu, who led the study.
Materials science and engineering professors Gerard Wong and Jianjun Cheng were
co-principal investigators on the study with Lu. Graduate students Rong Tong
(who is co-first author on the paper with Cao), Abhijit Mishra and Weichen Xu
also worked on the study.
Lu's laboratory specializes in isolating aptamers that bind to specific molecules
and converting them into effective sensors and diagnostic agents. His team used
an aptamer that binds to nucleolin receptors, which are found in abundance on
certain breast cancer cells. The researchers then developed an effective method
for attaching the aptamer to a liposome loaded with cisplatin, a drug that effectively
kills cancer cells but has troublesome side effects when administered intravenously.
Tests in cells grown in the lab yielded promising results. Four days after
they exposed the cells to the new drug-delivery system, 59.5 percent of the
breast cancer cells had died, while less than 12 percent of breast cancer cells
treated with cisplatin alone had died.
"By labeling a liposome that contains cisplatin with a cancer cell-specific
aptamer, we have shown delivery of the drugs to cancer cells without significant
damage to regular cells," Lu said, "making it possible to maximize
the drug potency while minimizing its side effects."
This approach "integrates the advantages of small molecules and antibodies,"
said Cheng, who helped pioneer the use of aptamers as targeting molecules for
drug delivery. "This is the first study to integrate the aptamers and the
Another advantage of using aptamers as targeting agents is that they are easily
disabled. They readily bind to complementary DNA, which prevents them from interacting
with cell receptors.
The new approach will be useful for many applications, Wong said. "What
we're really doing here is coming up with a general toolbox to deal with a broad
range of cancers."
"You can change aptamers to target a different type of cancer, you can
change the therapeutic molecules to fight cancer or other diseases, and you
can reverse the dose," Cheng said. "That's a lot of tools in the toolbox.
It has great potential."