Special Delivery: Using Nanotechnology to Target Cancer

This is the fourth in a series of articles highlighting some of the technologies, processes and keynote plenary sessions presented at the 2024 Annual Meeting of the Biomedical Engineering Society, October 2024.     

Since the early days of nanotechnology, researchers have dreamed of decorating nanoparticles so they would target specific cancers. Their small size could enable them to pass through cell walls to deliver medicine to tumors. Decades of experience has shown how challenging this dream was. The BMES session at the recent BMES 2024 Annual Meeting, “Cancer Drug Delivery & Nanotechnology,” looked at ways researchers are trying to surmount these problems. 

Biohybrid robots. One approach under development by Simone Scheurle, an associate professor at ETH Zurich, involves magnetically steering swarms of biohybrid robots toward a tumor. Her biohybrids are bacteria that contain naturally occurring or genetically functionalized magnetic materials. The bacteria could deliver drug treatments, but even without medications, they could compete for nutrients and slow tumor growth.

The problem is finding a way to get biohybrid robots through the surface of the endothelium. This lipid surface is somewhat elastic, and her team calculated that it would take about 10 piconewtons to push the bacteria across. This is about an order of magnitude higher than they could muster with their magnetic equipment.  

Instead of relying on brute force, Scheurle tried rotating the magnetic fields. This enabled the bacteria to “walk” across the surface of the endothelial lining and explore its surface to find gaps where they could cross.

To improve spatial selectivity, she used two opposing permanent magnets to cancel each other in the center. Then she superimposed a rotating magnetic field in the center. The resulting field moved like a trampoline, suppressing motion on the edges while walking biohybrid robots over the epithelium in the center. The end result was greater concentration of the biohybrids in the tumor. The setup also enabled provided process feedback through inductive detection. 

Ultrasound-sensitive hydrogels. Treating cancer noninvasively involves tradeoffs. Radiation therapy, for example, kills tumors but produces collateral damage to heathy tissue. Photodynamic therapy uses light to activate medicines only at tumor sites, so it is more precise. Unfortunately, light does not penetrate far enough to attack cancers deep in the body. 

An alternative is sonodynamic therapy. It uses low-intensity ultrasonic waves to activate ultrasound-sensitive chemicals, which create bubbles that burst and release reactive (molecular) oxygen that attack tumors. Cavitation near the tumor surface creates gaps that enable the deadly oxygen to enter the tumor cells. The problem with this approach is that the ultrasound waves can generate random gas bubbles that burst and harm healthy tissues.

University of Illinois, Urbana, postdoctoral researcher Yun-Sheng Chen has been working on a solution. It involves a new class of injectable hydrogel mechanochemical sensitizers that shows improved efficiency at lower ultrasound intensities. The material itself consists of an amine-functionalized silica core attached to mechanophores by an NHS-azo linker and coated with a polymer shell. 

Tests showed that a combination of the new sensitizer and focused ultrasound-controlled tumor growth over nine days in mice seeded with breast cancer. At 4.7 W/cm2, ultrasound intensities were well below tissue damage threshold yet, thanks to the sensitizer, they killed tumor cells efficiently.  

Fighting brain tumors. Anna Debski, a graduate student at University of Virginia, discussed the use of gene-embedded nanoparticles to treat glioblastoma, which accounts for 80 percent of all central nervous system cancers. Once diagnosed, the disease’s median survival rate is 17 months, even with surgical, radiation, or chemical treatment. 

Some researchers are testing gene therapy to repair mutations that cause the cancer. Genetic medicines are delivered with an experimental technique called convection enhanced delivery, basically running medication through narrow catheters surgically implanted in the brain.  

Nanoparticles may provide a nonsurgical alternative. Researchers often modify them with ligands to target one of several receptors on the tumor surface. Glioblastoma cells are unusually rich in surface thiols. Debski targets them by attaching thiol ligands to nanoparticles containing genetic medicines. This delivers the package to the surface, but it still has to cross the cellularly heterogeneous blood-brain barrier and the messy blood-tumor barrier.  

Her solution is focused ultrasound. It increased tumor cell transfection tenfold over intravenously injected nanoparticles, to the same level as convection enhanced delivery. Not only did ultrasound-driven nanoparticles avoid surgery but they also transfected a broader range of cells types than convection enhanced delivery. 

Killer cells are T-cell alternatives. T-cell therapy uses a patient’s own immune cells to fight cancer. Unfortunately, many cancer patients cannot generate enough T cells for this to work. Even when they do, the T cells must be activated by presenting them with antigens from the body’s own major histocompatibility complex, a difficult and time-consuming process.  

Some researchers have turned to killer cells for a less complex, off-the-shelf solution without potential allergic reactions. These are among the immune system’s first line of defense, and they attack both liquid and solid tumors. To harness K cells, however, investigators must first harvest and amplify them.  

Thereasa Raimondo, an assistant professor at Brown University, is investigating how to do this in vivo*. This would speed treatment, slash costs, eliminate the need for lymphodepleting chemotherapy, and improve patient outcomes.  

Her approach involves encapsulating small interfering RNA (siRNA) in a novel biodegradable lipid nanoparticle. It delivers siRNA directly to killer cells, where it silences the protein that inhibits K cell activation. 

Test results proved positive. Raimondo first injected mice with IL-15, a protein that turns on killer cells. Ordinarily, the mouse’s immune system jumps in and quickly silences this protein. When she injected the mouse with siRNA nanolipid, however, she silenced 70 percent of the proteins suppressing killer cells in vivo. Once activated, the killer cells also responded more strongly to further activation.  

In a 25-day test on mice infected with cancer, the IL-15 plus siRNA-nanolipid treatment significantly prolonged mouse survival.