Rhodojaponin III-Loaded Chitosan Derivatives-Modified Solid Lipid Nanoparticles for Multimodal Antinociceptive Effects in vivo
Qingyun Yang, Jian Yang, Shuigen Sun, Jingyi Zhao, Shuang Liang, Yi Feng, Minchen Liu, Jiquan Zhang
Abstract
Background: Rhodojaponin III (RJ-III) is a bioactive diterpenoid, which is mainly found in Rhododendron molle G. Don (Ericaceae), a potent analgesia in traditional Chinese medicine with several years of clinical applications in the country. However, its clinical use is limited by its acute toxicity and poor pharmacokinetic profiles. To reduce such limitations, the current study incorporated RJ-III into the colloidal drug delivery system of hydroxypropyl trimethyl ammonium chloride chitosan (HACC)-modified solid lipid nanoparticles (SLNs) to improve its sustained release and antinociceptive effects in vivo for oral delivery. Results: The optimized [email protected] were close to spherical, approximately 134 nm in size, and with a positive zeta potential. In vitro experiments showed that [email protected] were stable in the simulated gastric fluid and had a prolonged release in PBS (pH = 6.8). Pharmacokinetic results showed that after intragastric administration in mice, the relative bioavailability of [email protected] was 87.9%. Further, it was evident that the peak time, half-time, and mean retention time of [email protected] were improved than RJ-III after the administration. In addition, pharmacodynamic studies revealed that [email protected] markedly reduced the acetic acid, hot, and formalin-induced nociceptive responses in mice ( P < 0.001), and notably increased the analgesic time ( P < 0.01). Moreover, [email protected] not only showed good biocompatibility with Caco-2 cells in vitro but its LD 50 value was also increased by 1.8-fold as compared with that of RJ-III in vivo. Conclusion: These results demonstrated that [email protected] improved the pharmacokinetic characteristics of the RJ-III, thereby exhibiting toxicity-attenuating potential and antinociceptive enhancing properties. Consequently, HACC-SLNs loaded with RJ-III could become a promising oral formulation for pain management that deserves further investigation in the future. Graphical Abstract: Keywords: rhodojaponin III, multimodal antinociceptive, oral administration, solid lipid nanoparticles, hydroxypropyl trimethyl ammonium chloride chitosan, pharmacokinetic