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DURHAM, N.C. -- 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
easily.

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 –
molecular weight of 300 to 600 – 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
molecules.

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 and accumulation.

"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 – 2
million molecular weight -- achieved better concentrations in
tumors than a lower molecular weight, the study showed.

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
intestines.

"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."