(599bz) Sustained Delivery of Nerve Growth Factor By Amphiphilic Polyanhydride Micro/Nanoparticles to Enhance Peripheral Nerve Regeneration

Administration of various neurotrophic factors at the site of peripheral nerve injury (PNI) has been tested as a strategy to enhance the survival and regrowth of sprouting axons. Nerve growth factor (NGF) is among the factors which has shown great promise and improved the survivability of regenerating axons. Various methods of administering NGF include pumps, genetically modified cells to hypersecrete NGF, and also micro/nanoparticles fabricated using different types of natural and synthetic polymers. Most commonly used synthetic polymers are polyesters such as poly (lactic-co-glycolic acid) (PLGA), which often results in degradation of encapsulated proteins and also exhibits limited capacity for controlled release of bioactive molecules. During the last decade, polyanhydrides have been shown to offer better stabilization of various proteins and provide a controlled and sustained release of biological molecules. Polyanhydrides degrade by a mechanism of surface erosion and the byproducts formed are found to be biologically inert, non-toxic, nonmutagenic and creates a very low pH environment, unlike polyesters.

In this study, we have used 1,6-bis(p-carboxyphenoxy)hexane (CPH), 1,8-bis(p-carboxyphenoxy)-3,6-dioxaoctane (CPTEG) and sebacic acid (SA) to synthesize random amphiphilic copolymers of polyanhydrides such as 20:80 CPH:SA , 50:50 CPH:CPTEG, etc. Nerve growth factor-β (NGFβ) was used as a target protein to encapsulate using these micro/nanoparticles. Different methods such as spray drying and solid/oil/oil (S/O/O) were used for encapsulating NGFβ inside the nanoparticles.

These micro/nanoparticles showed a sustained release of NGFβ for up to a month. Different amphiphilic polymers degraded according to different release profiles. Using a cell viability assay (MTT assay) we showed that these particles were not cytotoxic to mesenchymal stem cells (MSCs) at concentrations of 125 µg/ml. The bioactivity of NGFβ released from micro/nanoparticles was tested using PC12 cells, where released NGFβ was found to enhance neurite outgrowth of PC12 cells as compared to blank micro/nanoparticles.

For future studies, we will implant these micro/nanoparticles in a nerve regeneration conduit in a rat sciatic nerve injury model to test their efficacy on enhancing nerve regeneration.