Nanocapsules with retinoic acid may treat MS inflammation: Study

Modified nanocapsules containing retinoic acid can suppress inflammation and prompt the growth of cells that produce nerve fibers’ myelin coating, which is lost in multiple sclerosis (MS), a cell-based study shows.

The results demonstrated how lipid (fat) nanocapsules that contain medicines can access the brain and treat the two hallmark features of MS — inflammation and myelin loss, called demyelination.

The cell-based study, “Functionalized retinoic acid lipid nanocapsules promotes a two-front attack on inflammation and lack of demyelination on neurodegenerative disorders,” was published in the Journal of Controlled Release.

MS is considered a demyelinating disease due to the progressive loss of the myelin sheath, which is caused by a self-reactive immune response that leads to inflammation, further damaging the sheath, nerve cells, and the myelin-producing cells, or oligodendrocytes.

Retinoic acid (RA), a product of vitamin A metabolism, has been used to stimulate the growth of brain cells from neural stem cells and to produce mature oligodendrocytes from oligodendrocyte progenitor cells. It can also modulate immune responses and promote regeneration in the nervous system.

These may make it an ideal candidate to target both the inflammatory response behind MS and to stimulate oligodendrocyte growth and restore myelin. RA is relatively unstable and prone to degradation, however.

Lipid nanocapsules (LNCs) are a drug delivery system that consists of a tiny core of fat molecules surrounded by a layer of surface molecules. LNCs are designed to protect therapeutics from degrading, to increase their stability and effectiveness.

They can also be modified to access the brain by targeting the transferrin receptor (TfR) on the surface of the cells that line the blood-brain barrier, a highly selective and protective membrane that controls which substances can get from the bloodstream into the brain.

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Encasing retinoic acid in lipid nanocapsules

Researchers at the University of Porto, Portugal, developed and tested LNCs containing retinoic acid and modified with a protein fragment (TfRp) that binds to the TfR. Their formulations were also loaded with super paramagnetic iron oxide nanoparticles (SPIONs) to guide the LNCs toward the brain using an external magnetic field close to the head.

First, toxicology tests identified a well tolerated range of LNC and retinoic acid concentrations using lines of human brain endothelial cells — which line the brain’s blood vessels — rat microglia cells, the brain’s immune cells, and rat oligodendrocyte precursor cells (OPCs).

In human endothelial cells, adding TfRp on the LNC surface improved cellular uptake by three to four times compared with unmodified cells, “suggesting the use of the TfR pathway to internalize the LNC,” the researchers wrote.

The TfR-mediated uptake was confirmed by adding TfRp alone that competed with the fragment at the surface of the nanocapsules, which reduced uptake. The uptake was also verified in microglia cells and OPCs.

The researchers then used a single layer of human endothelial cells as a model for the blood-brain barrier. Experiments showed that TfRp modification to LNCs containing retinoic acid and SPIONs significantly improved permeability by at least five times versus particles without the peptide or retinoic acid alone.

To test the impact of the TfRp-SPION-LNC RA system on inflammation, microglia cells were activated by LPS, a pro-inflammatory molecule. The treatment suppressed the production of three pro-inflammatory immune signaling proteins by up to six times, data showed. There was also a 100 times improvement in the production of the anti-inflammatory protein interleukin-10.

The presence of SPIONs within the LNCs didn’t impair the activity of the retinoic acid or affect the cells.

Finally, the lipid nanocapsules induced the transformation of rat OPCs into more mature, myelin-producing cells by up to five times, suggesting “RA is able to affect the behavior of oligodendrocytes, promoting the development of more mature oligodendrocytes,” the researchers said. “Overall, the results show that this nanosystem can act in both the inflammatory microenvironment present at the [brain and spinal cord] of affected patients, but also stimulate the differentiation of new oligodendrocytes, paving the way for a promising platform in the therapy of MS.”

More research was needed, the researchers said.

“Further work should be carried out now to validate the nanosystem [in living animals], to confirm the improved targetability towards the brain by the co-encapsulation of SPIONs, and to establish a proof-of-concept in a demyelinating disorder model,” they said.