Credit: Kathy Atkinson
Researchers have devised a novel way to deliver chemotherapy drugs “on demand,” according to a paper published in Proceedings of the National Academy of Sciences.
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, this one gradually releases a low level of the drug by diffusion over time. But the new hydrogel differs from others in a key way.
Researchers previously applied ultrasound to gels to temporarily increase doses of drug, but that approach was a one-shot deal, as the ultrasound was used to destroy those gels.
In the current study, the researchers used ultrasound to temporarily disrupt the gel so that it released short, high-dose bursts of the drug. 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 a way to administer drugs with a greater level of control than was possible before.
The researchers also demonstrated in lab cultures and in mouse models of breast cancer that the pulsed, ultrasound-triggered hydrogel approach to drug delivery was more effective at stopping the growth of tumor cells than traditional, sustained-release drug therapy.
“Our approach counters the whole idea of sustained drug release and offers a double whammy,” said study author David J. Mooney, PhD, of the Harvard School of Engineering and Applied Sciences in Boston.
“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.”
Self-healing hydrogel
Key to the researchers’ success in designing a hydrogel that self-heals was 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 tumors,” said study author Cathal Kearney, PhD, of the Royal College of Surgeons in Ireland. “The careful selection of materials and properties make it a reversible process.”
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 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 is in the presence of more calcium, the bonds reform and the gel self-heals.
Drug testing
Once the researchers knew the gel would self-heal, they tested out a drug they suspected it would hold well: the chemotherapy drug mitoxantrone.
Sure enough, the ultrasound triggered the gel to release the blue-colored drug, as indicated by the newly blue color of the surrounding medium. Just a single ultrasound dose was effective, and the gel reformed after it was disrupted, making multiple cycles possible.
Next, the team tested the treatment in mouse models of breast cancer. They injected the drug-laden gel close to the tumors.
Over the course of 6 months, the mice that received a low-level, sustained release of the drug with a daily concentrated pulse of ultrasound (2.5 minutes) fared significantly better than mice treated the same but without ultrasound.
In contrast to controls, the tumors in the ultrasound-treated mice did not grow substantially. And the mice survived for an additional 80 days.
Potential applications
The researchers believe their technique could help improve 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 than current methods, Dr Mooney said.
The researchers also found their hydrogel can release cargo other than drugs, including proteins and condensed plasmid DNA. This lays the groundwork for using these hydrogels for tissue regeneration and gene therapy.
Dr Mooney said he and his colleagues plan to explore these potential applications, as well as the possibility of unleashing 2 different drugs independently from the same hydrogel.
