Add PEG to make the drug go farther
the brain to fight the recurrence of human brain tumours.
The team from Cornell University and Yale University took the chemotherapy drug camptothecin and added the water-soluble polymer, polyethylene glycol (PEG). They found the drug-polymer conjugate could diffuse further in the brain and deliver 11 times more medication to the tumour than the plain drug alone. "Our modelling shows that PEGylation has the potential to increase treatment distances to more than a centimetre, which may be sufficient to prevent the recurrence of human brain tumours," the researchers said in a report to be published in the journal Bioconjugate Chemistry. Traditionally, treating diseases in the brain has been problematic due to the blood-brain barrier, which limits the systemic delivery of most drugs. Local administration via injection or implant has come some way to overcoming the blood-brain barrier, but distribution of the drug in the brain is slow, the drug only diffuses a few millimetres, and is often rapidly removed by capillaries resulting in a more than 10-fold drop in concentration. "Conjugation extends circulation time in the bloodstream, and additional attachment of protease-specific sequences can target release of the free drug . . . Since polyethylene glycol is known for its biocompatibility and its ability to solubilise hydrophobic molecules in water, we believe that PEG-drug conjugates show great potential for improving the brain distribution of drug released from controlled-release polymers," the authors said. The team looked at three models: the release of the drug on its own; the activity of the drug when permanently attached to a diffusible polymer; and the activity of the drug which is inactive when coupled by an ester bond to a polymer, which is then freed to become biologically active. According to the researchers, each of the models has the potential to improve the distribution of the drug in the brain, though the permanently attached drug had a reduced potency. The advantage of producing a PEG-drug conjugate was the conjugate had greater solubility than the drug by itself and had a much slower rate of elimination from the brain tissue, the report said. In theory, the study allows for the "rational design of future conjugates with optimal physical properties for the treatment of a cancer site". "Stability of the conjugation bond, activity of the drug-polymer conjugate, solubility of the conjugate relative to the drug, and molecular weight of the polymer must all be considered in the design of a conjugate to maximise drug distribution," the authors said.
