Dendrimers as oral drug transporters

UK research team improves beta blocker delivery using tree-like polymers.

Dendrimers, those tree-like polymers formed from branched monomers, may one day turn up in prescription drugs. Several studies have already shown that they can act as carriers for poorly soluble drug molecules, and even for DNA in gene therapy.

Researchers at the University of Manchester, UK, have now shown that packaging a drug in a dendrimer host not only makes it soluble but also allows it to bypass the transporter protein that would normally stop it from being absorbed in the intestines after it has been taken orally.

Antony D’Emanuele’s group is studying the uptake of propranolol (a beta blocker and anti-anxiety drug) using monolayers of a human cell line known as Caco-2 as a model system. The membrane transporter P-glycoprotein (P-gp) is known to reduce the uptake of propranolol when it is taken orally. While there are known P-gp inhibitors, it would be preferable to have the two functions in one molecule, because taking two drugs at a time adds to the uncertainties.

The researchers modified commercially available polyamidoamine (PAMAM) dendrimers by attaching lauroyl chains to their outer (third) shell, which reduced the toxicity of the dendrimers and improved uptake. Then they covalently attached the drug molecule to this construct.

Their detailed studies of the propranolol transport across a monolayer of Caco-2 cells showed that when the drug coupled to the dendrimer it can efficiently permeate the cells without being removed by the P-gp transporter. Each dendrimer molecule can carry between two and six propranolol molecules with the same efficiency.

While there is an obvious interest for pharmaceutical applications, and this research has been supported by AstraZeneca for the past six years, D’Emanuele is cautious about the prospects: ’We are quite a long way from clinical trials,’ he says, ’as all our work to date has been performed using cell cultures. We hope to be able to improve the bioavailability of drugs that cannot presently be delivered by the oral route.’

Michael Gross