Boosting Drug Permeability Across the Blood-Brain Barrier Through Supramolecular Macrocyclization

Area of Science:

• Medicinal Chemistry
• Supramolecular Chemistry
• Neuroscience

Background:

• The blood-brain barrier (BBB) tightly controls substance transport, hindering effective central nervous system (CNS) targeted therapies.
• Current treatments struggle with precise cellular targeting and efficient drug delivery across the BBB.

Purpose of the Study:

• To develop a novel strategy for synthesizing phenothiazine-based macrocycles with enhanced BBB permeability.
• To evaluate the therapeutic potential of these macrocycles against glioblastoma (GBM).

Main Methods:

• A streamlined one-step macrocyclization strategy was employed for phenothiazine synthesis.
• Supramolecular interactions within the macrocyclic cavity were investigated.
• In vitro and in vivo efficacy against GBM was assessed.

Main Results:

• The synthesized macrocycles demonstrated significantly enhanced BBB permeability and cellular uptake.
• These macrocycles exhibited superior anti-glioblastoma (GBM) activity compared to small-molecule analogs.
• Performance surpassed existing chemotherapeutics and nanomaterials in anti-GBM assays.

Conclusions:

• The one-step macrocyclization offers a promising framework for reengineering small molecules into advanced CNS therapeutics.
• This approach enhances BBB permeability and pharmacological properties for improved drug delivery.
• Phenothiazine-based macrocycles represent a new class of agents for treating brain tumors like GBM.