In the transition from benign to malignant, cancer cells transition from stiff to soft. Mechanotargeting harnesses mechanics to improve targeting efficiency of nanparticle-based therapeutic agents. Zhang lab/vecteezy.com
Diseased cells such as metastatic cancer cells have markedly different mechanical properties that can be used to improve targeted drug uptake, according to a team of researchers at Penn State.
Many labs around the world are developing nanoparticle-based drug delivery systems to selectively target tumors. They rely on a key-and-lock system in which protein keys on the surface of the nanoparticle click into the locks of a highly expressed protein on the surface of the cancer cell. The cell membrane then wraps around the nanoparticle and ingests it. If enough of the nanoparticles and their drug cargo is ingested, the cancer cell will die.
The adhesive force of the lock and key is what drives the nanoparticle into the cell, says Sulin Zhang, professor of engineering science and mechanics. “It is almost universal that whenever there is a driving force for a process, there always is a resistive force. Here, the driving force is biochemical – the protein-protein interaction.”
The resistive force is mechanical, the energy cost of the membrane wrapping around the nanoparticle. Until now, bioengineers only considered the driving force and designed nanoparticles to optimize the chemical interactions, a targeting strategy called “chemotargeting.” Zhang believes they should also take into account the mechanics of the cells to design nanoparticles to achieve enhanced targeting, which forms a new targeting strategy called “mechanotargeting.”
“These two targeting strategies are complementary; you can combine chemotargeting and mechanotargeting to achieve the full potential of nanoparticle-based diagnostic and therapeutic agents,” Zhang says. “The fact is that targeting efficiency requires a delicate balance between driving and resistive forces. For instance, if there are too many keys on the nanoparticle surface, even though these keys only weakly interact with the nonmatching locks on normal cells, these weak off-target interactions may still provide enough adhesion energy for the nanoparticles to penetrate the cell membrane and kill the healthy cells.” On the other hand, if the adhesion energy is not high enough, the nanoparticle won’t get into the cell.
In “Mechanotargeting: Mechanics-dependent Cellular Uptake of Nanoparticles,” published online ahead of print in the journal Advanced Materials, Zhang and company report the results of experiments on cancer cells grown on hydrogels of variable stiffness. On soft hydrogels the cells remained cohesive and benign and experienced a nearly constant stress that limited the uptake of the nanoparticles. But on stiff hydrogels the cells became metastatic and adopted a three-dimensional shape offering more surface area for nanoparticles to adhere, and became less stressed. Under this condition, the cells took up five times the number of nanoparticles as the benign cells.
“The nanoparticles are fluorescent, so we count the number of nanoparticles that get into the cell by the fluorescence intensity. We found that in the malignant cells the intensity is five times higher,” Zhang says. “That proves that mechanotargeting works.”
First author on the Advanced Materials paper is Qiong Wei, a Ph.D. student in Zhang’s group. Other coauthors are former Ph.D. students Changjin Huang and Yao Zhang, and current Ph.D. students Tiankai Zhao and Peng Zhao, also in Zhang’s group. Peter Butler, professor of biomedical engineering, Penn State, also contributed.
Support for this work was provided by the National Science Foundation and a National Institutes of Health grant to Butler and Zhang.
Contact Prof. Zhang at suz10@psu.edu.