Diblock Copolymers of Poly(ethylene oxide)- b-poly(propylene oxide) Stabilize a Blood-Brain Barrier Model under Oxidative Stress

The blood-brain barrier (BBB) is a highly restrictive barrier at the interface between the brain and the vascular system. Even under BBB dysfunction, it is extremely difficult to deliver therapies across the barrier, limiting the options for treatment of neurological injuries and disorders. To circumvent these challenges, there is interest in developing therapies that directly engage with the damaged BBB to restore its function. Previous studies revealed that poloxamer 188 (P188), a water-soluble triblock copolymer of poly(ethylene oxide) (PEO) and poly(propylene oxide) (PPO), partially mitigated BBB dysfunction in vivo. In the context of stabilization of the damaged BBB, the mechanism of action of PEO-PPO block copolymers is unknown, and there has been minimal exploration of polymers beyond P188. In this study, a human-based in vitro BBB model under oxidative stress was used to investigate polymer-BBB interactions since oxidative stress is closely linked with BBB dysfunction in many neurological injuries and disorders. PEO-PPO block copolymers of varied numbers of chemically distinct blocks, PEO block length, and functionality of the end group of the PPO block were assessed for their efficacy in improving key physiological readouts associated with BBB dysfunction. While treatment with P188 did not mitigate damage in the in vitro BBB model, treatment with three diblock copolymers improved barrier integrity under oxidative stress to a similar extent. Of the considered variations in the block copolymer design, the reduction in the number of chemically distinct blocks had the strongest influence on therapeutic function. The demonstrated efficacy of three alternative PEO-PPO diblock copolymers in this work reveals the potential of these polymers as a class of therapeutics that directly treat the damaged BBB, expanding the options for treatment of neurological injuries and disorders.