Scientists have devised a blueprint for boosting anti-cancer drugs' effectiveness
and lowering their toxicity by attaching the equivalent of a lead sinker onto
the drugs. This extra weight makes the drugs penetrate and accumulate inside
tumors more effectively.
Chemotherapy drugs often fall short of achieving
their full impact because the drugs diffuse in and
out of the tumor too rapidly, said the scientists
from Duke University Medical Center and Duke's Pratt
School of Engineering.
The scientists increased the size of the drug by
adding a "macromolecular weight" that increases its
concentration and staying power inside the tumor.
The heavier molecules are more selectively absorbed
by tumors because tumor blood vessels are more permeable
or "leakier" than normal blood vessels. Thus, larger
molecules can pass through the tumor vessels more
Drugs with a greater molecular weight also reduce
chemotherapy's toxicity to healthy tissue because
the large molecules cannot easily permeate normal
blood vessels. As a result, normal tissue receives
less of the drug than does the tumor.
Results of the study, funded by the National Institute
of Biomedical Imaging and Bioengineering, a branch
of the National Institutes of Health, are published
in the March 1, 2006, issue of the Journal of the
National Cancer Institute.
"Small molecules penetrate the tumor very efficiently,
but are also removed very efficiently," said Ashutosh
Chilkoti, Ph.D, a Duke biomedical engineer and senior
author of the study. "Larger molecules penetrate
more slowly, but they stay in the tissue longer,
giving the patient a greater concentration of the
drug. If you balance the two factors with a precise
weight, you get optimal drug concentration."
Chilkoti said current chemotherapy drugs are so
small ï¿½ molecular weight of
300 to 600 ï¿½ that they are reabsorbed
into the bloodstream before their anti-cancer effects
are fully achieved.
Overcoming this limitation by adding macromolecular
weight is not a new concept, but determining the
precise weight to achieve optimal drug concentration
has proved difficult, he said. Chilkoti and his colleagues
in the department of biomedical engineering and radiation
oncology at Duke measured the tumor permeability,
penetration and accumulation of various macromolecular
weights in mouse tumors. The drug carrier they studied
was dextran, essentially a chainlike string of sugar
By measuring a range of dextran molecular weights
in a three-dimensional model and over 30 minutes
instead of a single time point, they determined the
optimal weight for tumor permeability, penetration
"No one has previously quantified the process of
three-dimensional penetration and accumulation as
it occurs -- information that is critical to achieving
optimal results," said Matthew Dreher, a graduate
student in biomedical engineering and lead author
of the study. "We quantified tumor blood vessel permeability
and we examined precisely where in the tumor the
macromolecular molecules accumulated."
The optimal molecular weight for the drug's highest
accumulation inside tumors was between 40,000 and
70,000, the study showed. At this weight, a large
percentage of the drug was concentrated near the
blood vessels of the tumor, where cancer cells tend
to proliferate more rapidly. Drugs of lower molecular
weight penetrated more deeply into the tumor but
exited more quickly.
"Tumor cells multiply more rapidly near the vasculature,
so targeting that area is key to chemotherapy's cancer-killing
effects," said Mark Dewhirst, DVM, Ph.D., a co-author
of the paper who is a radiation biologist and director
of the Duke Hyperthermia Program. Dewhirst's team
has illuminated numerous mechanisms by which a tumor's
blood vessels and oxygen levels influence its growth
and its demise.
"Artificially increasing the weight of a drug gives
us a means to increase the amount of drug going to
the tumor while reducing toxicity to the rest of
the body," said Fan Yuan, Ph.D., co-author on the
paper and an associate professor of biomedical engineering
at Duke. "We can adjust the weight higher or lower
depending upon where we want the drug to concentrate."
Even drugs with vastly elevated molecular weights ï¿½ 2
million molecular weight -- achieved better concentrations
in tumors than a lower molecular weight, the study
Chilkoti said chemotherapy by itself is small enough
to travel throughout the body via the bloodstream,
causing toxicity to vital organs such as the liver,
bone marrow and heart. Likewise, chemotherapy's stay
inside tumors is brief because it flows out as rapidly
as it entered.
In contrast, high molecular weight chemotherapy
molecules are too large to be picked up by normal
blood vessels. The drugs also remain longer in the
tumor because they are not readily reabsorbed into
the bloodstream, nor can they penetrate the kidneys
to be cleared from the body. They must wait for the
liver to break them up and dispose of them via the
"Our goal was to increase the tumor dose and lower
the systemic dose," said Chilkoti. "Macromolecular
drug carriers are an attractive drug delivery system,
because they target tumors and have limited toxicity
in normal tissues."
Of additional benefit, macromolecular drug carriers
can be substituted for the toxic substances routinely
mixed with chemotherapy to make it more soluble.
Macromolecular molecules can selectively carry the
drug to the tumor simply due to their size and do
not need such noxious carriers, said Chilkoti.
"We can increase the solubility of chemotherapy
by adding it to a soluble macromolecular molecule," he
said. "Then you don't have to mix it with noxious
substances as a means of ensuring that chemotherapy
gets into cancer cells."
Chilkoti said their findings also are important
because they can be used to optimize drug delivery
of all macromolecular therapeutic agents, including
cytokines, antibodies and anti-angiogenic drugs."
Contact: Kendall Morgan