An In-Vitro Model for Sustained Bupivacaine and Dexamethasone Nanoparticle Co-Therapy

Vollständiger Abstract

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Abstract Purpose In the absence of a reliable cure, Osteoarthritis (OA), treatment targets symptomatic pain and inflammation. However, chronically administered drugs often result in adverse side effects. In order to develop an improved treatment, our studies focused on controlled dual drug delivery. Bupivacaine (BUP), a local anesthetic, is used to manage pain directly and dexamethasone (DEX), a glucocorticoid, reduces inflammation. Key obstacles of both BUP and DEX administration, is that at high concentrations both drugs may be toxic, while at low concentrations they can provide pain relief and control inflammation for only a short time. Methods We developed nanoparticles composed of Poly(lactic- co-glycolic acid) (PLGA), a biodegradable polymer, to prolong the release of lower doses of BUP and DEX for at least 30 days. Using the nanoparticle (NP) diffusion profiles, loading capacity, and optimal dose for our target cell types, we tested our dual NP therapy on chondrocytes, macrophages, and in baseline and activated co-cultures in order to compare bolus and NP drug effects either alone or in combination. Results We found that the combined nanoparticle co-therapy maintained cell viability and reduced inflammation more than either DEX nanoparticle (DexNP) or BUP nanoparticle (BupNP) therapy alone, especially in co-culture, and can therefore ultimately be incorporated into longer term therapeutic protocols. Pathway analysis enabled an approach to understanding the potential synergy between the two drugs. Conclusion Overall, the macrophage, chondrocyte, and co-culture studies indicate that DualNP therapy maintains viability while reducing IL-8 secretion more than either DexNP, BupNP, and bolus DUAL in all conditions. While further analysis is needed, due to its versatility, our approach can be further developed to potentially improve an array of clinical outcomes.