Cornell researchers have developed a new way to safely heat up specific areas inside the body by using biodegradable polymers that contain tiny water pockets, which are then activated by near-infrared laser. The technology could lead to precise and noninvasive diagnostics and therapeutics, perhaps to fight cancer.
The findings were reported May 23 in ACS Nano, a publication of the American Chemical Society. The lead author is postdoctoral researcher Jinha Kwon.
The project began when Zhiting Tian, associate professor of mechanical and aerospace engineering in Cornell Engineering and the paper's senior author, wanted to apply her lab's expertise in nanoscale thermal transport and energy conversion - which has applications ranging from microelectronics to space exploration - to biomedicine.
First, she needed to find the right delivery system.
In 2014, she came across a paper about polylactic-co-glycolic acid (PLGA) polymers that could be triggered by near-infrared light and release drugs. The polymer itself couldn't absorb near-infrared light, but the authors hypothesized that perhaps water was trapped inside it and that confined water was what reacted to the light and enabled the drug release. That approach was particularly intriguing to Tian because, unlike the gold nanorods or semiconducting polymers that have been used for similar purposes, PLGA polymers are biodegradable - so they won't pose any long-term risk to the body, and they are already approved by the Food and Drug Administration.
Tian was eager to test their hypothesis, but at the same time, she was still stuck on where and how to apply PLGA as a local heater. In 2022, she saw a study from a team led by professor Guosong Hong at Stanford University that used near-infrared light to heat up temperature-sensitive ion channels and control targeted deep-brain neural activities. The pieces began to fit together.
"I got very excited about that work because if the neuron activities can be activated or inhibited by localized heating, that means we could use those PLGA particles for that purpose," Tian said.
She decided she wanted to learn more, so she did a very academic thing. She went back to school - and spent a semester in Stanford for her sabbatical.
"I visited the group whose paper I read, and I stayed in their lab. I went to meetings, I watched them doing the experiments and I attended the class the PI taught every week," Tian said. "It felt so good to be a student again, and I could take notes and learn all those new concepts. It was fun."
Tian returned to Cornell with a deeper understanding of neuromodulation and how to combine it with her lab's work in measuring thermal transport and her materials background.
But one area her team hadn't much experience with was conducting in vitro cell experiments, so they turned to the lab of Nozomi Nishimura, associate professor of biomedical engineering in Cornell Engineering, for experimental support.
The researchers tried two different methods - single and double emulsion - to produce the PLGA nanoparticles. They ultimately found that single emulsion - whereby water pockets are not introduced intentionally, but rather high-frequency sound waves cause water molecules to diffuse into the particles, becoming confined - resulted in smaller water pockets that, counterintuitively, could reach a higher temperature.
"The trick is the water behaves differently when confined in the tiny spaces. It heats up more efficiently than the normal bulk water," Tian said. "And we have a polymer layer that acts like a thermal insulator to trap the heat inside and keeps it from escaping too quickly."
That process provides the necessary contrast between the photothermal agent, i.e., the confined water in the polymer, and the cellular environment, producing localized heat.
In addition to neuromodulation, another promising application of the technology is hyperthermia therapy, in which cancer cells are destroyed by heat so that chemotherapy and radiation treatment can be more effective.
"You want to be very targeted, local and precise, and increase the temperature of the cancerous cells, but without hurting the healthy tissues," Tian said. "For now, we can sort of understand what's going on with the fundamental mechanisms inside. We did the cellular test so we can see that the particles are safe, and they don't interfere with the key cellular functions. I think the next big step is to move to in vivo testing, where we apply this to animal models and see the impact."
Co-authors include Nishimura; master's degree students Xinzhu Huang and Jaejun Lee; doctoral student Jiyoung Kim; postdoctoral researchers Prithwish Biswas and Keehun Kim; and research associate Chi-Yong Eom.
The research was supported by Cornell's McManus Fund. The researchers made use of the Cornell Center for Materials Research and the Cornell Biotechnology Resource Center.
