title: 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.
authors.affiliation: Department of Orthopaedics, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, People's Republic of China; Institute of Spine, Shanghai University of Traditional Chinese Medicine, Shanghai, People's Republic of China.
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Orthopaedics, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, People's Republic of China; Institute of Spine, Shanghai University of Traditional Chinese Medicine, Shanghai, People's Republic of China.
authors.forename: Tengteng
authors.initials: T
authors.lastname: Wang
authors.affiliation: Department of Orthopaedics, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, People's Republic of China; Institute of Spine, Shanghai University of Traditional Chinese Medicine, Shanghai, People's Republic of China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Li
authors.affiliation: Biochemistry and Molecular Biology, School of Life Science, East China Normal University, Shanghai, People's Republic of China.
authors.forename: Jing
authors.initials: J
authors.lastname: Huang
authors.affiliation: Department of Orthopaedics, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, People's Republic of China; Institute of Spine, Shanghai University of Traditional Chinese Medicine, Shanghai, People's Republic of China.
authors.forename: Hao
authors.initials: H
authors.lastname: Xu
authors.affiliation: Department of Orthopaedics, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, People's Republic of China; Institute of Spine, Shanghai University of Traditional Chinese Medicine, Shanghai, People's Republic of China.
authors.forename: Jinlong
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Orthopaedics, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, People's Republic of China; Institute of Spine, Shanghai University of Traditional Chinese Medicine, Shanghai, People's Republic of China.
authors.forename: Yongjun
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Orthopaedics, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, People's Republic of China; Institute of Spine, Shanghai University of Traditional Chinese Medicine, Shanghai, People's Republic of China.
authors.forename: Qianqian
authors.initials: Q
authors.lastname: Liang
mesh_terms: D000818:Animals; D018501:Antirheumatic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D017209:Apoptosis / Q000187:drug effects; D001219:Aspartate Aminotransferases / Q000378:metabolism; D004224:Diterpenes / Q000008:administration & dosage* / Q000009:adverse effects; D004337:Drug Carriers / Q000008:administration & dosage* / Q000009:adverse effects / Q000737:chemistry; D016503:Drug Delivery Systems / Q000379:methods; D004852:Epoxy Compounds / Q000008:administration & dosage / Q000009:adverse effects; D005260:Female; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D053761:Nanocomposites / Q000008:administration & dosage / Q000737:chemistry; D010616:Phenanthrenes / Q000008:administration & dosage* / Q000009:adverse effects; D010649:Phenylalanine / Q000031:analogs & derivatives / Q000737:chemistry; D011099:Polyglutamic Acid / Q000031:analogs & derivatives / Q000737:chemistry
chemical_list: D018501:Antirheumatic Agents; D004224:Diterpenes; D004337:Drug Carriers; D004852:Epoxy Compounds; C505757:L-phenylalanine ethylester; D010616:Phenanthrenes; C511775:poly(gamma-glutamic acid); C508283:poly(gamma-glutamic acid)-graft-phenylalanine ethylester copolymer; C001899:triptolide; D011099:Polyglutamic Acid; D010649:Phenylalanine; D001219:Aspartate Aminotransferases
keywords: drug carrier system; poly-γ-glutamic acid; toxicity; triptolide