title: A renal-targeted triptolide aminoglycoside (TPAG) conjugate for lowering systemic toxicities of triptolide.
abstract: Triptolide (TP), a naturally derived compound, is proven effective in the treatment of nephritis and chronic allograft nephropathy. However, the severe multiorgan toxicity greatly limited it from further clinic use. 2-Glucosamine was demonstrated as a potential targeting ligand that could specifically interact with megalin receptors highly expressed in renal proximal tubules. In this study, 2-glucosamine was employed as a glycosyl donor while triptolide the acceptor to afford a nonhydrolyzable triptolide derivative-triptolide aminoglycoside (TPAG). The kidney-targeting efficiency, pharmacodynamic properties and safety of TPAG were thus evaluated. TPAG displayed 6.94-fold of AUC(0-t, kidney) and 13.96-fold of MRT(0-t, kidney) compared to TP. Additionally, TPAG presented improved protective effect against renal ischemia/reperfusion injury. Compared to TP's multiorgan toxicity, TPAG showed minimum toxicity toward the kidney and genital systems, and greatly lowered toxicity in the liver and immune systems. In sum, our study presented an alternative structure modification of triptolide with improved safety and efficacy profiles.
authors: Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, State Key Laboratory of Biotherapy, Sichuan University, Chengdu 610041 Sichuan, China.
authors: Bowen
authors: B
authors: Qi
authors: Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, State Key Laboratory of Biotherapy, Sichuan University, Chengdu 610041 Sichuan, China.
authors: Xinyi
authors: X
authors: Wang
authors: Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, State Key Laboratory of Biotherapy, Sichuan University, Chengdu 610041 Sichuan, China.
authors: Yangyang
authors: Y
authors: Zhou
authors: Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, State Key Laboratory of Biotherapy, Sichuan University, Chengdu 610041 Sichuan, China.
authors: Qiao
authors: Q
authors: Han
authors: Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, State Key Laboratory of Biotherapy, Sichuan University, Chengdu 610041 Sichuan, China.
authors: Ling
authors: L
authors: He
authors: Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, State Key Laboratory of Biotherapy, Sichuan University, Chengdu 610041 Sichuan, China.
authors: Tao
authors: T
authors: Gong
authors: Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, State Key Laboratory of Biotherapy, Sichuan University, Chengdu 610041 Sichuan, China.
authors: Xun
authors: X
authors: Sun
authors: Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, State Key Laboratory of Biotherapy, Sichuan University, Chengdu 610041 Sichuan, China.
authors: Yao
authors: Y
authors: Fu
authors: Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, State Key Laboratory of Biotherapy, Sichuan University, Chengdu 610041 Sichuan, China. Electronic address: zrzzl@vip.sina.com.
authors: Zhirong
authors: Z
authors: Zhang
mesh_terms: D000617:Aminoglycosides / Q000737:chemistry* / Q000493:pharmacokinetics; D000818:Animals; D004224:Diterpenes / Q000633:toxicity*; D004852:Epoxy Compounds / Q000633:toxicity; D005944:Glucosamine / Q000737:chemistry*; D007668:Kidney / Q000187:drug effects* / Q000473:pathology; D007687:Kidney Tubules, Proximal / Q000187:drug effects; D008099:Liver / Q000187:drug effects; D008297:Male; D051379:Mice; D015394:Molecular Structure; D010616:Phenanthrenes / Q000633:toxicity*; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000188:drug therapy; D013737:Testis / Q000187:drug effects; D018675:Toxicity Tests
chemical_list: D000617:Aminoglycosides; D004224:Diterpenes; D004852:Epoxy Compounds; D010616:Phenanthrenes; C001899:triptolide; D005944:Glucosamine
keywords: 2-Glucosamine; Glycosidic bond; Low toxicity; Renal-targeting; Triptolide