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Weighting cancer drugs to make them hit tumors harder

his 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
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Source:Duke University


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