title: Liver-targeting Resibufogenin-loaded poly(lactic-co-glycolic acid)-D-α-tocopheryl polyethylene glycol 1000 succinate nanoparticles for liver cancer therapy.
abstract: Liver cancer remains a major problem around the world. Resibufogenin (RBG) is a major bioactive compound that was isolated from Chansu (also called toad venom or toad poison), which is a popular traditional Chinese medicine that is obtained from the skin secretions of giant toads. RBG has strong antitumor effects, but its poor aqueous solubility and its cardiotoxicity have limited its clinical use. The aim of this study was to formulate RBG-loaded poly(lactic-co-glycolic acid) (PLGA)-D-α-tocopheryl polyethylene glycol 1000 succinate nanoparticle (RPTN) to enhance the treatment of liver cancer. RPTN, RBG-loaded PLGA nanoparticle (RPN), and RBG/coumarin-6-loaded PLGA-D-α-tocopheryl polyethylene glycol 1000 succinate nanoparticle (RCPTN) were prepared. The cellular uptake of RCPTN by HepG2 and HCa-F cells was analyzed using confocal laser scanning microscopy. Apoptosis was induced in HepG2 cells by RPTN, RBG solution (RS), and 5-fluorouracil solution (used as the negative controls), as assayed using flow cytometry. LD50 (median lethal dose) values were determined for RS and RPTN, and the liver-targeting properties were determined for RCPTN in intravenously injected mice. A pharmacokinetic study was conducted in rats, and the in vivo therapeutic effects of RPTN, RPN, and RS were examined in a mouse tumor model. The results showed that RCPTN simultaneously delivered both coumarin-6 and RBG into HepG2 and HCa-F cells. The ratio of apoptotic cells was increased in the RPTN group. The LD50 for RPTN was 2.02-fold higher than the value for RS. Compared to RS, RPTN and RPN both showed a significant difference in vivo not only in the pharmacodynamic study but also in anticancer efficacy, and RPTN performed much better than RPN. The detection indexes for drug concentration and fluorescence inversion microscopy images both demonstrated that RCPTN was much better at targeting the liver than RS. The liver-targeting RPTN, which displayed enhanced pharmacological effects and decreased toxicity for the loaded drug RBG, is therefore a promising intravenous dosage form that may be useful in the treatment of liver cancer.
authors: College of Pharmacy, Dalian Medical University, Dalian, People's Republic of China.
authors: Qiuchen
authors: Q
authors: Chu
authors: College of Basic Medical Sciences, Dalian Medical University, Dalian, People's Republic of China.
authors: Hong
authors: H
authors: Xu
authors: College of Pharmacy, Dalian Medical University, Dalian, People's Republic of China.
authors: Meng
authors: M
authors: Gao
authors: College of Pharmacy, Dalian Medical University, Dalian, People's Republic of China.
authors: Xin
authors: X
authors: Guan
authors: College of Pharmacy, Dalian Medical University, Dalian, People's Republic of China.
authors: Hongyan
authors: H
authors: Liu
authors: College of Pharmacy, Dalian Medical University, Dalian, People's Republic of China.
authors: Sa
authors: S
authors: Deng
authors: College of Pharmacy, Dalian Medical University, Dalian, People's Republic of China.
authors: Xiaokui
authors: X
authors: Huo
authors: College of Pharmacy, Dalian Medical University, Dalian, People's Republic of China.
authors: Kexin
authors: K
authors: Liu
authors: College of Pharmacy, Dalian Medical University, Dalian, People's Republic of China.
authors: Yan
authors: Y
authors: Tian
authors: College of Pharmacy, Dalian Medical University, Dalian, People's Republic of China.
authors: Xiaochi
authors: X
authors: Ma
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002018:Bufanolides / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology; D003374:Coumarins / Q000008:administration & dosage / Q000737:chemistry; D004337:Drug Carriers / Q000008:administration & dosage / Q000737:chemistry; D056945:Hep G2 Cells / Q000187:drug effects; D006801:Humans; D019344:Lactic Acid / Q000737:chemistry*; D008113:Liver Neoplasms / Q000188:drug therapy*; D008297:Male; D051379:Mice; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry; D011100:Polyglycolic Acid / Q000737:chemistry*; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D017207:Rats, Sprague-Dawley; D013844:Thiazoles / Q000008:administration & dosage / Q000737:chemistry; D014810:Vitamin E / Q000008:administration & dosage / Q000737:chemistry*
chemical_list: D000970:Antineoplastic Agents; D002018:Bufanolides; D003374:Coumarins; D004337:Drug Carriers; D013844:Thiazoles; C517282:coumarin 6; D014810:Vitamin E; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; C005734:bufogenin; C014225:tocophersolan
keywords: HCa-F cells; HepG2 cells; PLGA-TPGS; Resibufogenin; liver cancer; nanoparticles