This article has been reviewed according to Science X's editorial process and policies. Editors have highlighted the following attributes while ensuring the content's credibility: A new Northwestern Medicine study has uncovered key molecular design principles that could help supramolecular therapeutics cross the blood-brain barrier, a major challenge for this novel approach to treating neurological disorders. Published in ACS Nano, the study examined how subtle changes in the structure of molecules called peptide amphiphiles affect their ability to move through brain endothelial cells and traverse the blood-brain barrier.
The findings provide a roadmap for developing new therapies capable of reaching the brain, including potential treatments for stroke, Alzheimer's disease, Parkinson's disease and other neurological conditions. Samuel Stupp, Ph.D., the Board of Trustees Professor of Materials Science and Engineering, Chemistry, Medicine and Biomedical Engineering, was senior author of the study. The blood-brain barrier protects the central nervous system by controlling which substances can enter brain tissue from the bloodstream.
While this protection is essential for health, it also blocks the vast majority of drugs from reaching their intended targets in the brain. To better understand how the structure of nanoscale therapeutics affects their ability to cross the blood-brain barrier, scientists led by Stupp studied peptide amphiphiles that shared the same peptide sequence but had different lipid tail lengths. By varying the tails, the team was able to change the cohesion of the supramolecular therapies while keeping the peptide sequences unchanged.
Their experiments showed that structures with longer lipid tails formed more stable, tightly bound nanostructures. Those nanostructures accumulated inside brain endothelial cells but tended to remain trapped there. In contrast, nanostructures with shorter lipid tails were able to cross cell layers in an in vitro model of the blood-brain barrier.
The study also found evidence that the structures could disassemble during transport and then reassemble after crossing the barrier, allowing therapeutic nanostructures to potentially reach brain tissue while retaining their functionality. "If they are designed correctly, they enter as an assembly into the cell, and then they get distributed in different compartments, particularly when they go to the lysosome," said Stupp, director of the Center for Regenerative Nanomedicine. "Then they start swimming within the cell, not as an assembly, but more as individual molecules or very small aggregates of molecules." The investigators observed that once the molecules exited the cells, they "recognized" each other and reformed into functional nanostructures.
According to Stupp, the team's results suggest that successful brain delivery of therapeutic supramolecular assemblies requires a balance between stability and the dynamic adaptability needed to reach their targets. Nanostructure therapies that are too cohesive become stuck within endothelial cells, while less cohesive structures can break apart, move through cellular compartments and continue their journey. "When they are exocytosed from the cell, they are not an assembly, but once they're out, they find each other and reassemble at their targets," Stupp said.
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