Image: Harvard researchers have shown how ultrasound can temporarily disrupt an alginate hydrogel, which is held together by calcium ions (black dots) that are bound to acid chains (yellow). The gel self-heals when the ultrasound stops (Photo courtesy of the Wyss Institute and Harvard SEAS).
Image: Fluorescence micrographs show red-colored breast cancer cells that were exposed to three different treatments. The use of ultrasound to trigger periodic bursts of higher drug doses (right) was most effective in killing the cancer cells (Photo courtesy of the Wyss Institute and Harvard SEAS).
Modern 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 gradual approach and offers a unique way to locally deliver the drugs “on demand.”
The study’s findings were reported online ahead of print June 24, 2014, in the journal Proceedings of the National Academy of Sciences of the United States of America (PNAS).
Led by David J. Mooney, PhD, a core faculty member at Harvard University’s Wyss Institute for Biologically Inspired Engineering and a professor of bioengineering at the Harvard School of Engineering and Applied Sciences (SEAS; Cambridge, MA, USA), the scientists packed a biocompatible hydrogel with a chemotherapy drug and used ultrasound to trigger the gel to release the agent. Similar to many other injectable gels that have been employed for drug delivery for decades, this one slowly releases a low level of the agent by diffusion over time. To temporarily increase doses of drug, scientists had earlier applied ultrasound--but that strategy was a one-shot job as the ultrasound was used to destroy those gels. However, this gel was different.
The investigators used ultrasound to temporarily disrupt the gel such that it released short, high-dose bursts of the drug--similar 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. Furthermore, the investigators also demonstrated in lab cultures and in mice with breast cancer tumors that the pulsed, ultrasound-triggered hydrogel approach to drug delivery was more effective at blocking the growth of tumor cells than conventional, sustained-release drug therapy.
“Our approach counters the whole idea of sustained drug release, and offers a double whammy,” said Prof. 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 potential 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, according to Prof. 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 Nathanial Huebsch, PhD, who was a Harvard SEAS graduate student in the Harvard-Massachusetts Institute of Technology (MIT; Cambridge, MA, USA) division of health sciences and technology at the time of the research. 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 success of the project was devising 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 tumors,” said co-lead author Cathal Kearney, PhD, who was a postdoctoral fellow at SEAS at the time of the study. “The careful selection of materials and properties make it a reversible process,” Dr. Kearney said.
The scientists performed most of their research for this study with a gel composed 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 correct level of ultrasound waves, the bonds break up and enable the gel to release its drug payload, but as long as the gel in in the presence of more calcium, the bonds reform and the gels self-heal.
Once the researchers figured out that the gel would self-heal, they evaluated a drug that they believed it would hold well—in this instance, a chemotherapy drug called mitoxantrone, which is frequently used to treat breast cancer. In fact, the ultrasound triggered the gel to release the blue-colored drug, as indicated by the newly blue color of the surrounding medium. Only one ultrasound dose was effective, and the gel reformed after it was disrupted, making multiple cycles possible.
Next, they tested the treatment on mice that had human breast cancer tumors implanted in their bodies. They injected the drug-laden gel close to the tumors, and over the course of six months the mice that received a low-level sustained release of the drug with a daily concentrated pulse of ultrasound (only 2.5 minutes) fared significantly better than mice treated the same but without ultrasound. In contrast to the other groups, the tumors in the ultrasound-treated mice did not grow substantially and, moreover, the mice survived for an additional 80 days.
“These results demonstrate how applying novel engineering approaches and programmable nanomaterials can create entirely new solutions to critical medical problems,” said Wyss Institute rounding director Don Ingber, MD, PhD, who is also a professor of vascular biology at Harvard Medical School and Boston Children’s Hospital (Boston, MA, USA), and professor of bioengineering at Harvard SEAS. “Dave’s work shows that these new responsive hydrogels that remodel reversibly when exposed to ultrasound energy at the nanoscale not only provide a new way to administer drugs on demand, they also produce better responses to therapy even in a disease as difficult to treat as cancer.”
This development to use simple ultrasound pulses and readily available hydrogels in a new way comes after Prof. Mooney’s work using low-power lasers to stimulate stem cells to regenerate the material that comprises teeth. The scientists also demonstrated that the gel can release other kinds of cargo as well, including proteins, which lays the foundation for potentially using these hydrogels for tissue regeneration, and condensed plasmid DNA, suggesting their potential use in gene therapy.
The scientists next plan to examine these other potential applications, as well as the possibility of releasing two different drugs independently from the same hydrogel, according to Prof. Mooney.
Harvard University School of Engineering and Applied Sciences