Non-Invasive, Epicortical Delivery of Brain-Derived Neurotrophic Factor for Recovery after Stroke

Eric Ho (1, 2, 5), Jaclyn Obermeyer (1, 2, 5), Anup Tuladhar (1, 5), Samantha Payne (1, 5),

CINDI MORSHEAD(1, 4, 5) Molly Shoichet (1, 2, 3, 5)

1. Institute of Biomaterials and Biomedical Engineering, University of Toronto

2. Department of Chemical Engineering and Applied Chemistry, University of Toronto

3. Department of Chemistry, University of Toronto

4. Department of Surgery, University of Toronto

5. Donnelly Centre for Cellular and Biomolecular Research, University of Toronto

Stroke affects over 15 million people worldwide, and despite significant research patients are faced with limited treatment options. This is due, in part, to the blood brain barrier (BBB). To address this roadblock, our group has developed a non-invasive, epicortical drug delivery vehicle that circumvents the BBB to provide therapeutic effects to the central nervous system. The system was used to deliver brain-derived neurotrophic factor (BDNF), a promising protein therapeutic for stroke therapy that does not readily cross the BBB. We have shown that BDNF can be electrostatically adsorbed onto the negative surface of poly(lactic co-glycolic acid) (PLGA) nanoparticles dispersed in a hyaluronan-methylcellulose hydrogel, limiting protein denaturation while achieving a similar release profile to encapsulation in vitro. We hypothesized that the vehicle could be applied in vivo to deliver BDNF in an endothelin-1 rat model of stroke injury.

Release from the vehicle in vitro resulted in a sustained, burst free release for 30 days, with the discharged BDNF bioactive when released from the vehicle. In vivo, significant BDNF diffusion into the tissue was observed, with the protein detected up to a depth 3000 µm up to 21 days post treatment. BDNF delivery augmented plasticity after stroke, as evidenced by increased synaptophysin staining in the contralesional hemisphere of BDNF-treated rats, as well as reduced lesion volume, indicating a neuroprotective effect. When assessing behavioural recovery, hindlimb function was significantly enhanced at 7 weeks with local BDNF delivery.

This vehicle is highly tunable for the delivery of many therapeutic proteins. The controlled release is encapsulation free and governed by electrostatic interactions between PLGA and charged proteins, enabling significantly higher protein loading and lower loss of bioactivity. Release rate and dose can be controlled through modification of the PLGA nanoparticles. In vivo, a therapeutically relevant concentration of BDNF was delivered to the brains of stroke injured rats with an epicortical hydrogel-nanoparticle composite. With local, sustained delivery directly to the brain, we demonstrate the benefit of BNDF and the potential for use of this platform strategy with other biotherapeutics.