Fabrication of novel vesicles of triptolide for antirheumatoid activity with reduced toxicity in vitro and in vivo

Abstract

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.

Effect of Triptolide on Dextran Sodium Sulfate-Induced Ulcerative Colitis and Gut Microbiota in Mice

“…After 1 week of adaptive feeding, the mice from the control group (Con) and DSS group (Mod) were administered normal saline. The mice from positive control group (Mes) received mesalazine (50 mgċkg −1 ċday −1 ), or the mice received triptolide at high [0.4 mg/kg, Triptolide (TP)1 group], medium (0.2 mg/kg, TP2 group), or low (0.1 mg/kg, TP3 group) dose (Qianqian et al, 2016). After 3 days, the drinking water for all groups except the Con group was supplemented with 3% DSS for 7 days (the average daily drinking water consumption per mouse is about 4.3-4.5 ml).…”

Triptolide Modulates the Expression of Inflammation-Associated lncRNA-PACER and lincRNA-p21 in Mycobacterium tuberculosis–Infected Monocyte-Derived Macrophages

“…Indeed, lincRNA-p21 plays a crucial role in stress and DNA damage response through the induction of p53-dependent cell cycle arrest and apoptosis in numerous cell types ( Huarte et al, 2010 ; Dimitrova et al, 2014 ; Tu et al, 2017 ; Jin et al, 2019 ). On the other hand, triptolide is a cytotoxic compound that induces DNA damage, cell cycle arrest, apoptosis, and autophagy in several cell types ( Park and Kim, 2013 ; Zhang et al, 2016 ; You et al, 2018 ). Our results are in line with previous reports that indicated increased lincRNA-p21 expression in several cells and tissues exposed to genotoxic agents ( Recio et al, 2013 ; Gezer et al, 2014 ; Tang et al, 2015 ).…”

“…This diterpene triepoxide possesses antitumor, immune-suppressive, and anti-inflammatory activities which it exerts via several mechanisms in a tissue-, context-, and disease-specific manner ( Zhao et al, 2010a ; Zhao et al, 2010b ; Liu, 2011 ; Carter et al, 2012 ; Tamgue et al, 2013 ; Wu et al, 2013 ; Hou et al, 2017 ; Tamgue and Lei, 2017 ; Chen et al, 2018 ; Yang et al, 2018 ; Huang et al, 2019 ; Yuan et al, 2019 ; Zhao et al, 2019 ). Notably, triptolide exerts its cytotoxic activities through induction of DNA damage, cell cycle arrest, apoptosis, and autophagy in several cell types ( Park and Kim, 2013 ; Zhang et al, 2016 ; You et al, 2018 ). Its anti-inflammatory activities result among other mechanisms from the downregulation of NF-kb– and AP-1–controlled pro-inflammatory molecules such as TNF-α, IL-6, IL-12, and Ptgs-2 in several cell types, including macrophages and dendritic cells ( Chun and Surh, 2004 ; De Moraes et al, 2007 ; Liu et al, 2007 ; Lu et al, 2014 ; Wang et al, 2014 ; Chen et al, 2018 ).…”

Triptolide mitigates radiation-induced pneumonitis via inhibition of alveolar macrophages and related inflammatory molecules

“…Although the high toxicity of TPL, including liver and kidney toxicity and myelosuppression [ 36 ], has limited its clinical use thus far, several promising solutions have been developed to increase its therapeutic potential. Zhang L et al synthesized and in vitro and in vivo tested a nanodrug carrier system (γ-PGA-l-PAE-TPL) that delivers a less toxic form of TPL [ 37 ]. Fidler et al developed MRx102, a TPL lipophilic derivative, that is 20-fold to 60-fold safer than TPL in rat models yet maintains its anticancer activity at nanomolar concentrations [ 34 , 38 ].…”