Researchers have developed drug-loaded nanoparticles that selectively target the cells responsible for causing damaging inflammation following a spinal cord injury. Given to mice soon after an injury, the novel therapy reduced inflammation and improved motor function, opening the door to new therapeutic possibilities for people with spinal injuries.
Sustaining a spinal cord injury (SCI) is devastating enough, but the subsequent inflammation and the damage it causes to the spinal cord can worsen the clinical outcome. This secondary injury can develop over time and lead to paraplegia or quadriplegia that may not have been present at the time of the primary injury.
Research has shown that in the first days after SCI, microglial cells are activated and proliferate, causing secondary injury via the production of pro-inflammatory cytokines. These cells and their cytokines activate destructive astrocyte cells that further exacerbate inflammation. Microglia and astrocytes are subtypes of glial cells, the non-neuronal cells of the brain and nervous system.
Developing effective immune-based therapies that selectively target glial cells has been challenging. However, researchers at the Mario Negri Institute for Pharmacological Research, in collaboration with the Polytechnic University of Milan, have developed novel nanogel-based nanoparticles that target these cells and release an active compound that reduces inflammation.
The nanoparticles were synthesized using polymers and loaded with the drug Rolipram, a phosphodiesterase 4 (PDE4) inhibitor, before being placed into a nanogel carrier. PDE4 regulates the body’s production of pro-inflammatory cytokines. The resultant drug-loaded nanoparticles had a mean diameter of 168 nm.
The researchers induced inflammation in cultures of mice and human glial cells and treated them with their Rolipram-loaded nanoparticles. Using an innovative microscopic technique called ExM, which allows super-resolution imaging of nanoparticles at the subcellular level, the researchers could see how the drug-loaded nanoparticles interacted with cells and the biological effects they produced. They found that the nanoparticles were internalized by the microglia and astrocytes but not taken up by other cells.
They then tested their nanoparticles on mice with SCI, administering treatment either one day or 14 days post-injury. When given a day after injury, the nanogel loaded with Rolipram caused significant improvements in the mice’s motor performance on day seven, compared to the untreated group. However, when it was given 14 days post-injury, there was no therapeutic advantage; in fact, motor performance was significantly worse in these mice on days 28 and 35. This suggests that the treatment is more effective when started in the early subacute phase rather than later.
The Rolipram treatment carried by the nanoparticles reduced the production of inflammatory cytokines by microglia and astrocytes. Early treatment caused large numbers of microglia to migrate to the site of spinal cord damage but did not alter astrocyte behavior. Later treatment led to a reduced number of microglia at the injury site and did not modify astrocytes.
“The results of the study show that the nanogels reduced inflammation and improved recovery capacity in animal models with injury to the spinal cord, partially restoring motor functionality,” said Pietro Veglianese, the study’s corresponding author. “These results open the way to new therapeutic possibilities for spinal cord injured patients. Furthermore, this approach be advantageous for treating neurodegenerative diseases such as Alzheimer’s, in which inflammation and glial cells play a significant role.”
The study was published in the journal Advanced Materials.
