Fabrication of novel vesicles of triptolide for antirheumatoid activity with reduced toxicity in vitro and in vivo. Zhang Li,Wang Tengteng,Li Qiang,Huang Jing,Xu Hao,Li Jinlong,Wang Yongjun,Liang Qianqian International journal of nanomedicine Triptolide (TP) displays a strong immunosuppression function in immune-mediated diseases, especially in the treatment of rheumatoid arthritis. However, in addition to its medical and health-related functions, TP also exhibits diverse pharmacological side effects, for instance, liver and kidney toxicity and myelosuppression. In order to reduce the side effects, a nano drug carrier system (γ-PGA-l-PAE-TP [PPT]), in which TP was loaded by a poly-γ-glutamic acid-grafted l-phenylalanine ethylester copolymer, was developed. PPT was characterized by photon scattering correlation spectroscopy and transmission electron microscopy, which demonstrated that the average diameter of the drug carrier system is 98±15 nm, the polydispersity index is 0.18, the zeta potential is -35 mV, and the TP encapsulation efficiency is 48.6% with a controlled release manner. The methylthiazolyldiphenyl-tetrazolium bromide assay and flow cytometry revealed that PPT could decrease toxicity and apoptosis induced by free TP on RAW264.7 cells, respectively. The detection of reactive oxygen species showed that PPT could decrease the cellular reactive oxygen species induced by TP. Compared with the free TP-treated group, PPT improved the survival rate of the mice (P<0.01) and had no side effects or toxic effects on the thymus index (P>0.05) and spleen index (P>0.05). The blood biochemical indexes revealed that PPT did not cause much damage to the kidney (blood urea nitrogen and creatinine), liver (serum alanine aminotransferase and aspartate aminotransferase), or blood cells (P>0.05). Meanwhile, hematoxylin and eosin staining and terminal-deoxynucleotidyl transferase dUTP nick-end labeling staining indicated that PPT reduced the damage of free TP on the liver, kidney, and spleen. Our results demonstrated that PPT reduced free TP toxicity in vitro and in vivo and that it is a promising fundamental drug delivery system for rheumatoid arthritis treatment. 10.2147/IJN.S104593

Fabrication of a triptolide-loaded and poly-γ-glutamic acid-based amphiphilic nanoparticle for the treatment of rheumatoid arthritis. Zhang Li,Chang Junli,Zhao Yongjian,Xu Hao,Wang Tengteng,Li Qiang,Xing Lianping,Huang Jing,Wang Yongjun,Liang Qianqian International journal of nanomedicine Triptolide (TP) exhibits immunosuppressive, cartilage-protective and anti-inflammatory effects in rheumatoid arthritis. However, the toxicity of TP limits its widespread use. To decrease the toxic effects, we developed a novel nano-drug carrier system containing TP using poly-γ-glutamic acid-grafted di-tert-butyl L-aspartate hydrochloride (PAT). PAT had an average diameter of 79±18 nm, a narrow polydispersity index (0.18), a strong zeta potential (-32 mV) and a high drug encapsulation efficiency (EE=48.6%) and loading capacity (EE=19.2%), and exhibited controlled release (=29 h). The MTT assay and flow cytometry results indicated that PAT could decrease toxicity and apoptosis induced by free TP on RAW264.7 cells. PAT decreased lipopolysaccharides/interferon γ-induced cytokines expression of macrophage (<0.05). In vivo, PAT accumulated at inflammatory joints, improved the survival rate and had fewer side effects on tumor necrosis factor α transgenic mice, compared to TP. The blood biochemical indexes revealed that PAT did not cause much damage to the kidney (urea nitrogen and creatinine) and liver (alanine aminotransferase and aspartate aminotransferase). In addition, PAT reduced inflammatory synovial tissue area (<0.05), cartilage loss (<0.05), tartrate-resistant acid phosphatase-positive osteoclast area (<0.05) and bone erosion (<0.05) in both knee and ankle joints, and showed similar beneficial effect as free TP. In summary, our newly formed nanoparticle, PAT, can reduce the toxicity and guarantee the efficacy of TP, which represents an effective drug candidate for RA with low adverse side effect. 10.2147/IJN.S151233