Nanoparticles designed with complementary chemical and mechanical forces improve the targeting of tumors with cancer-fighting drugs.
Several labs over the last few years have attempted to use nanoparticle technologies to deliver cancer-fighting drugs directly to tumor cells. The idea is simple: Nanoparticles containing therapeutic agents lock onto specific proteins on the surface of cancer cells. That biochemical reaction instructs the cell membrane to ingest the nanoparticles. When enough nanoparticles are “eaten” and have delivered their drug cargo they can kill off the malignant cell.
But Sulin Zhang, professor of engineering science and mechanics at Pennsylvania State University, says such strategies haven’t reached their full potential. While scientists have focused on the biochemical interactions of cell proteins and nanoparticles, a process called chemotargeting, they have ignored something equally as important: the mechanical properties of healthy and diseased cells.
“There have been a lot of efforts to deliver chemotherapy agents directly to cells,” Zhang says. “But the nanoparticle-based agents developed haven’t been good enough. Many labs work on the adhesion of the nanoparticle of the cell, the adhesion energy. You need that chemical adhesion energy to drive the nanoparticle into the cell interior so it can do its work. But you also need to understand the mechanical energy of the cell, the resistive force of the cell, the thing that will allow the membrane to wrap around the nanoparticle and not resist its uptake.”
Zhang, whose lab focuses on applying mechanical engineering concepts into medical applications, believes that, for best uptake results, nanoparticles should be designed with complementary chemical and mechanical forces in mind. That translates into a combination of both chemo- and mechanotargeting. To show the latter’s importance, he and his colleagues tested fluorescent nanoparticle uptake on cancer cells cultured on hydrogels with varying degrees of stiffness. The mechanical properties of the cells grown on the hydrogels are altered, but chemical properties are left unchanged.
“The chemical properties of these cells are the same,” he says. “But now we’ve placed these cells on a different mechanical environment and the cells respond to that environment and change their mechanical properties. The nanoparticles are fluorescent, so we can see how many of the nanoparticles get into the cell.
They found, on the stiffer hydrogels, the cells became softer and assumed a three-dimensional shape, metastatic in nature, that offered more surface area for nanoparticles to attach. This resulted in cells taking up five times the number of nanoparticles than the cells cultured on softer environments. The cells grown on softer hydrogels, on the other hand, had harder membranes that limited the uptake of the nanoparticles. This proves that mechanotargeting is critical to creating optimal nanoparticle drug delivery systems, Zhang says.
“There is an energy cost when the cell takes in these nanoparticles,” he says. “And when we design these systems, we need to consider that energy cost. Take malaria-infected red blood cells for example. They are very stiff. But maybe we could add a drug of some sort to make them softer, find some way to manipulate the mechanical properties of those infected cells to facilitate this mechanotargeting in a way to complement the biochemical interactions.”
Zhang says, for too long, the biomedical engineering community has mainly looked at chemotargeting in biomedical applications. But he hopes this paper will help them understand the importance of the mechanical properties of diseased cells to create more effective drug delivery systems in the future.
“You can think of it almost like a car,” he says Zhang. “You can get the car, put gas in the engine, and off you go. But if there is a big physical barrier in front of you, it doesn’t matter how fast the car goes, how good that chemical driving force is. You can’t go forward unless you find a way to deal with that resisting force, the barrier. Mechanotargeting is complementary to chemotargeting. And we can use these forces together to make nanoparticle designs much more effective and efficient.”
Kayt Sukel is an independent technology writer.