Delivering drugs deeper

A Princeton University-led research team has developed a process to create particles that can deliver medicine deep into the lungs or infiltrate cancer cells while leaving normal ones alone.

The particles, which are 100 to 300 nanometres wide, can be loaded with medicines or imaging agents, like gold and magnetite, that will enhance the detection capabilities of CT scans and MRIs.

‘The intersection of materials science and chemistry is allowing advances that were never before possible,’ said Robert Prud’homme, a Princeton chemical engineering professor. ‘No one had a good route to incorporate drugs and imaging agents in nanoparticles.’

The new technique, dubbed ‘Flash NanoPrecipitation,’ allows the researchers to mix drugs and materials that encapsulate them. Similar mixing techniques have previously been used to create bulkier pharmaceutical products and have proven practical on a commercial scale. The Princeton-led team is the first to apply the technology to the creation of nanoparticles.

The nanoparticles are too large to pass through the membrane of normal cells, but will pass through larger defects in the capillaries of rapidly growing solid tumours, Prud’homme said. They could also improve the delivery of inhaled drugs because they are large enough to remain in the lungs, but too small to trigger the body’s lung-clearing defence systems.

In NanoPrecipitation, two streams of liquid are directed toward one another in a confined area. The first stream consists of an organic solvent that contains the medicines and imaging agents, as well as a polymer chain containing both hydrophopic and hydrophilic molecules. The second stream of liquid contains pure water.

When the streams collide, the hydrophobic medicines, metal imaging agents and polymers precipitate out of solution in an attempt to avoid the water molecules. The polymers immediately self-assemble onto the drug and imaging agent cluster to form a coating with the hydrophobic portion attached to the nanoparticle core and the hydrophilic portion stretching out into the water. By carefully adjusting the concentrations of the substances, as well as the mixing speed, the researchers are able to control the sizes of the nanoparticles.

The stretched hydrophilic polymer layer keeps the particles from clumping together and prevents recognition by the immune system so that the particles can circulate through the bloodstream. The hydrophobic interior of the particles ensures that watery environments do not immediately degrade them, though water molecules will, over time, break the particles apart, dispersing the medicine.

Ideally, the particles would persist for six to 16 hours after they were administered intravenously, Prud’homme said, which would theoretically allow enough time for the potent packages to slip into the solid tumour cells they encountered throughout the body.

In the lab, this is precisely the amount of time it takes for water molecules to work their way into the centres of the nanoparticles and degrade them. The team made their particles even more resistant to early degradation by attaching hydrophobic substances, including vitamin E, to the medicines and imaging agents before incorporating them into the particles. Further studies of the controlled release technique currently are under way.

Prud’homme’s technique is essentially the opposite of previous techniques for improving drug delivery, which is to attach molecules to drugs to make them more water-soluble. ‘Our advance is to use this technique and turn it around so the drugs stay inside our particles until we want them to leave,’ he said.