Development of tanshinone IIA chitosan nanoparticles via chitosan solid dispersion for improving the therapeutical effects

Tanshinone IIA, an important active ingredient isolated from Salvia miltiorrhiza , exhibits a broad spectrum of biological activities including anti-inflammatory, anti-oxidative, and anti-tumor. However, its poor water solubility results in low bioavailability and limits the subsequent clinical application. Chitosan nanoparticle is an excellent drug delivery carrier due to the ideal biocompatibility and pH-sensitive. Here, we developed an innovative and efficient approach to fabricate the tanshinone IIA-chitosan nanoparticles (TA/CS-NPs) by initially creating a tanshinone IIA-chitosan solid dispersion as the precursor for nanoparticle synthesis. This method successfully overcame the problem that the hydrophobic tanshinone IIA could not be directly mixed with the hydrophilic chitosan to prepare nanoparticles. The optimal conditions for TA/CS-NPs preparation were obtained through the response surface method, with the chitosan concentration of 31 mg/ml, the mass ratio of CS to TA 27:1, and stirring time 30 min. In vitro release and cell uptake experiments proved that the TA/CS-NPs had pH-sensitive drug release property. In ph5.0 dissolution medium or the medium of inflammatory cell, the nanoparticles revealed rapid drug release properties. However, in the ph7.4 dissolution medium or the medium of normal cells, the drug release rate of nanoparticles was very slow. Subsequently, cellular experiments demonstrated that the anti-inflammatory and antioxidant activities of tanshinone IIA were markedly enhanced through nanoparticle delivery. Compared with direct administration of tanshinone IIA, TA/CS-NPs have more significant activity on the inhibition of inflammatory factors (IL-1β, IL-6, TNF-α and NO), regulation of oxidative stress products (ROS, MDA) and antioxidant products (SOD, GSH, and CAT), protective effect on mitochondrial damage, inhibition of inflammatory signaling pathways (p-p65, NLRP3). This study provides a successful method to encapsulate hydrophobic drugs into hydrophilic chitosan nanoparticles and improve the therapeutic activities of the loaded drug.