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. 2012 Jun 28;160(3):666-75.
doi: 10.1016/j.jconrel.2012.03.024. Epub 2012 Apr 4.

Enhanced neurotrophin-3 bioactivity and release from a nanoparticle-loaded composite hydrogel

Jason C Stanwick  1 , M Douglas Baumann, Molly S Shoichet
Affiliations

Enhanced neurotrophin-3 bioactivity and release from a nanoparticle-loaded composite hydrogel

Jason C Stanwick et al. J Control Release. .

Abstract

Neurotrophin-3 (NT-3) has shown promise in regenerative strategies after spinal cord injury; however, sustained local delivery is difficult to achieve by conventional methods. Controlled release from poly(lactic-co-glycolic acid) (PLGA) nanoparticles has been studied for numerous proteins, yet achieving sustained release of bioactive proteins remains a challenge. To address these issues, we designed a composite drug delivery system comprised of NT-3 encapsulated in PLGA nanoparticles dispersed in an injectable hydrogel of hyaluronan and methyl cellulose (HAMC). A continuum model was used to fit the in vitro release kinetics of an NT-3 analog from a nanoparticle formulation. Interestingly, the model suggested that the linear drug release observed from composite HAMC was due to a diffusion-limiting layer of methyl cellulose on the particle surface. We then studied the effects of processing parameters and excipient selection on NT-3 release, stability, and bioactivity. Trehalose was shown to be the most effective additive for stabilizing NT-3 during sonication and lyophilization and PLGA itself was shown to stabilize NT-3 during these processes. Of four excipients tested, 400g/mol poly(ethylene glycol) was the most effective during nanoparticle fabrication, with 74% of NT-3 detected by ELISA. Conversely, co-encapsulation of magnesium carbonate with NT-3 was the most effective in maintaining NT-3 bioactivity over 28 days according to a cell-based axonal outgrowth assay. Together, the modeling and optimized processing parameters provide insight critical to designing a controlled bioactive release formulation for ultimate testing in vivo.

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