Novel Brain-Derived Neurotrophic Factor Controlled-Release Formulation Promotes Neuroprotection In Vitro

Abstract

Traumatic brain injury (TBI) leads to a cascade of primary and secondary neurodegenerative events, often causing lifelong disabilities. Brain-derived neurotrophic factor (BDNF) is a potential therapeutic for functional recovery of neurons. Unfortunately, BDNF is unstable and expensive, making direct infusion impractical. Therefore, we sought to develop a controlled release formulation to deliver BDNF. Our therapeutic construct encapsulates BDNF in poly(lactic-co-glycolic acid) nanoparticles (PLGA NPs), and further encapsulates these NPs in an alginate hydrogel. Encapsulating BDNF within NPs protects and assists in drug delivery, while further encapsulating the BDNF-NPs in alginate enables localization and sustained release. The BDNF-NPs were synthesized and evaluated for size, stability and BDNF release profile. A MATLAB model was developed to determine the approximate quantity of BDNF-NPs needed to evaluate therapeutic efficacy in neurons injured with hydrogen peroxide. We then compared the therapeutic efficacy and BDNF release profile of these BDNF-NPs to our novel alginate/BDNF-NP formulation. We have successfully designed and fabricated a double encapsulation positionally controllable construct that preserves BDNF bioactivity and extends its release. We also demonstrated that very low dosages of BDNF may be equally effective in promoting neuroprotection, thereby potentially reducing therapeutic costs without compromising efficacy. Our novel formulation offers a promising avenue for treating severe TBI and other neurological disorders which would benefit from a long-lasting and positionally controllable neuroprotective treatment. This approach can easily accommodate additional biologics for localized drug delivery with minimal re-formulation.