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 the 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, ’77 PhD, 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 with 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 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 necessary dynamic adaptability required 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
The work builds on previous research from Stupp’s laboratory, which recently demonstrated that a supramolecular therapeutic delivered in an animal model of stroke was able to reach the brain. The new study was designed to understand the molecular mechanisms and necessary structural features that enable transport across the blood-brain barrier.
“Our platform is a completely new modality of therapeutics,” Stupp said.
Unlike conventional small-molecule drugs, supramolecular therapeutics may contain thousands of molecules organized into nanoscale structures, he said.
Stupp said the findings could have uses beyond brain delivery. Understanding how supramolecular assemblies temporarily disassemble and reassemble could enable multiple routes of administration, including intravenous, intranasal and potentially oral delivery.
“This ACS Nano paper is a very important paper to us because we learned the molecular structure principles that are needed for this process,” Stupp said.
Looking ahead, the team plans to apply those principles to therapeutic nanostructures designed for specific neurological diseases. One area of interest is developing assemblies that can recognize and remove misfolded proteins implicated in neurodegenerative disorders.
“That’s where we’re going next,” Stupp said. “Designing the assemblies to be highly functional for a specific disease target.”
The study was supported by the Center for Regenerative Nanomedicine. Additional support came from the Chemistry of Life Processes Predoctoral Training Program at Northwestern University.
