3 min readDelivering Drugs on Cue
Boston, MA — Current drug-delivery systems used to administer chemotherapy to cancer patients typically release a constant dose of the drug over time – but a new study challenges this “slow and steady” approach and offers a novel way to locally deliver the drugs “on demand,” as reported in the Proceedings of the National Academy of Sciences (PNAS).
Led by Dr. David J. Mooney, a Core Faculty member at Harvard’s Wyss Institute for Biologically Inspired Engineering and the Robert P. Pinkas Family Professor of Bioengineering at the Harvard School of Engineering and Applied Sciences (SEAS), the team loaded a biocompatible hydrogel with a chemotherapy drug and used ultrasound to trigger the gel to release the drug. Like many other injectable gels that have been used for drug delivery for decades, this one gradually releases a low level of the drug by diffusion over time. To temporarily increase doses of drug, scientists had previously applied ultrasound — but that approach was a one-shot deal as the ultrasound was used to destroy those gels.
This gel was different.
The team used ultrasound to temporarily disrupt the gel such that it released short, high-dose bursts of the drug – akin to opening up a floodgate. But when they stopped the ultrasound, the hydrogels self-healed. By closing back up, they were ready to go for the next “on demand” drug burst – providing an innovative way to administer drugs with a far greater level of control than possible before. That’s not all. The team also demonstrated in lab cultures and in mice with breast cancer tumours that the pulsed, ultrasound-triggered hydrogel approach to drug delivery was more effective at stopping the growth of tumour cells than traditional, sustained-release drug therapy.
“Our approach counters the whole idea of sustained drug release, and offers a double whammy,” said Mooney. “We have shown that we can use the hydrogels repeatedly and turn the drug pulses on and off at will, and that the drug bursts in concert with the baseline low-level drug delivery seems to be particularly effective in killing cancer cells.”
The advance holds promising implications for improved cancer treatment and other therapies requiring drugs to be delivered at the right place and the right time — from post-surgery pain medications to protein-based drugs that require daily injections. It requires an initial injection of the hydrogel, but the approach could be a much less traumatic, minimally invasive and more effective method of drug delivery overall, Mooney said.
“We want to give clinicians the ability to deliver drugs as locally as possible combined with the flexibility to temporally control the dose,” said co-lead author Dr. Nathanial Huebsch, who was a Harvard SEAS graduate student in the Harvard-MIT Division of Health Sciences and Technology at the time of the research and is now a Postdoctoral Fellow at the Gladstone Institute of Cardiovascular Disease in San Francisco. For example, many cancer patients require a regular dose of pain killers, but unpredictable pain attacks require them to take much larger doses over a short time.
Key to the team’s success in designing a hydrogel that self-heals is choosing the right kind of hydrogel with the right kind of drug – and applying the right intensity of ultrasound.
“We were able to trigger our system with a level of ultrasound that was much lower than high-intensity focused ultrasound that is used clinically to heat and destroy tumours,” said co-lead author Dr. Cathal Kearney, who was a Postdoctoral Fellow at SEAS at the time of the study. He is now a Senior Research Fellow at the Royal College of Surgeons in Ireland (RCSI). “The careful selection of materials and properties make it a reversible process,” Kearney said.
The team carried out the majority of their work for this study with a gel made out of alginate, a natural polysaccharide from algae that is held together with calcium ions. In a series of laboratory tests they found that with the right level of ultrasound, the bonds break up and enable the gel to release its drug cargo – but as long as the gel in in the presence of more calcium, the bonds reform and the gels self-heal.
Once the team knew the gel would self-heal, they tested out a drug they suspected it would hold well – in this case a chemotherapy drug called mitoxantrone, which is often used to treat breast cancer. Sure enough, the ultrasound triggered the gel to release the blue-coloured drug, as indicated by the newly blue colour of the surrounding medium. Just a single ultrasound dose was effective, and the gel reformed after it was disrupted, making multiple cycles possible.
Article adapted from a Wyss Institute for Biologically Inspired Engineering at Harvard news release.