Chitosan derivatives modified solid lipid nanoparticles prolonged Rhodojaponin-III active time and enhanced the safety and multimodal analgesic effects in vivo

Abstract Background Rhodojaponin III (RJ-III), a bioactive diterpene, is a characteristic component of Rhododendron molle G. Don (Ericaceae), a potent analgesia in traditional Chinese medicine with thousands of years of clinical applications. However, its clinical use is limited by its acute toxicity and poor pharmacokinetic profile. To reduce such limitations, we 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 analgesic properties in vivo for oral delivery. Results The optimized RJ-III@HACC-SLNs were close to spherical, approximately 134 nm in size, with a positive zeta potential. In vitro experiments showed that RJ-III@HACC-SLNs were stable in the simulated gastric fluid, and were prolonged release in PBS (pH = 6.8). Pharmacokinetics results showed that after intragastric administration in mice, the relative bioavailability of RJ-III@HACC-SLNs was 87.9%, the peak time, half-time, and mean retention time of RJ-III@HACC-SLNs were significantly improved. Pharmacodynamic studies revealed that RJ-III@HACC-SLNs markedly reduced the acetic acid, hot, and formalin-induced nociceptive responses in mice (P < 0.001), and significantly increased the analgesic time (P < 0.01). Moreover, RJ-III@HACC-SLNs not only showed good biocompatibility with Caco-2 cells in vitro, but its LD50 value was also increased by 1.8-fold compared to RJ-III in vivo. Conclusions This study indicated that RJ-III@HACC-SLNs could exhibit certain toxicity-attenuating and effectiveness-enhancing effects by improving pharmacokinetic characteristics of the RJ-III, which could be a new strategy for intragastric delivery and analgesic treatment of RJ-III and HACC-modified SLNs, and provide a dosage form reference for the further study of RJ-III.