title: Improve bile duct-targeted drug delivery and therapeutic efficacy for cholangiocarcinoma by cucurbitacin B loaded phospholipid complex modified with berberine hydrochloride.
abstract: In present study, a novel phospholipid complex loaded cucurbitacin B modified with berberine hydrochloride (CUB-PLC-BER) was prepared by a simple solvent evaporation method with the aim of improving bile duct-targeted drug delivery and therapeutic efficacy for cholangiocarcinoma (CC). The complex's physicochemical properties were systemically investigated in terms of scanning electron microscopy (SEM), x-ray diffraction (XRD) and infrared absorption spectroscopy (IR). In vivo and in vitro antitumor studies, CUB-PLC-BER and the unmodified cucurbitacin B-phospholipid complex (CUB-PLC) presented stronger antitumor efficacy against human cholangiocarcinoma cells (QBC939 cells) than free cucurbitacin B (CUB), while phospholipids (PL) itself had no significant toxicity. Besides that, CUB-PLC showed the advantage over the free CUB and CUB-PLC-BER with regard to the inhibition of tumor growth in vivo antitumor study. Failure to establish the orthotopic CC model, the study attempted to measure the level of CUB in plasma and in bile to explore bile duct-targeted effect indirectly. In the pharmacokinetics study in rats, the average values of Cmax and AUC0-8h of CUB-PLC-BER group in rat bile were higher than those of CUB-PLC, while an opposite result was found in plasma. Meanwhile, the Cmax, AUC0-8h and AUC0-24h of CUB were the least both in plasma and in bile. The results indicated that the CUB-PLC-BER tended to provide a high and prolonged drug concentration to bile duct, and PL played a central role in internalizing CUB into cells to improve the water insoluble drug's permeability, which was of great benefit to enhance the bioavailability of CUB and improve therapeutic efficacy of CC. These results elucidated the potential of CUB-PLC-BER as drug delivery system for improving bile duct-targeted and therapeutic efficacy for CC.
authors.affiliation: 302 Hospital of PLA&PLA Institute of Chinese Materia Medica, Beijing 100039, China; Pharmacy College, Chengdu University of Traditional Chinese Medicine, Chengdu, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Cheng
authors.affiliation: 302 Hospital of PLA&PLA Institute of Chinese Materia Medica, Beijing 100039, China.
authors.forename: Ping-hua
authors.initials: PH
authors.lastname: Xu
authors.affiliation: 302 Hospital of PLA&PLA Institute of Chinese Materia Medica, Beijing 100039, China.
authors.forename: Bao-de
authors.initials: BD
authors.lastname: Shen
authors.affiliation: 302 Hospital of PLA&PLA Institute of Chinese Materia Medica, Beijing 100039, China; Pharmacy College, Chengdu University of Traditional Chinese Medicine, Chengdu, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Shen
authors.affiliation: 302 Hospital of PLA&PLA Institute of Chinese Materia Medica, Beijing 100039, China; Pharmacy College, Chengdu University of Traditional Chinese Medicine, Chengdu, China.
authors.forename: Juan-juan
authors.initials: JJ
authors.lastname: Li
authors.affiliation: 302 Hospital of PLA&PLA Institute of Chinese Materia Medica, Beijing 100039, China; Pharmacy College, Chengdu University of Traditional Chinese Medicine, Chengdu, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Qiu
authors.affiliation: 302 Hospital of PLA&PLA Institute of Chinese Materia Medica, Beijing 100039, China; Pharmacy College, Chengdu University of Traditional Chinese Medicine, Chengdu, China.
authors.forename: Chao-yong
authors.initials: CY
authors.lastname: Liu
authors.affiliation: 302 Hospital of PLA&PLA Institute of Chinese Materia Medica, Beijing 100039, China. Electronic address: yhlpharm@126.com.
authors.forename: Hai-long
authors.initials: HL
authors.lastname: Yuan
authors.affiliation: 302 Hospital of PLA&PLA Institute of Chinese Materia Medica, Beijing 100039, China. Electronic address: hanjin302emba@163.com.
authors.forename: Jin
authors.initials: J
authors.lastname: Han
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D001599:Berberine / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D001646:Bile / Q000737:chemistry; D001650:Bile Duct Neoplasms / Q000188:drug therapy*; D001652:Bile Ducts / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D018281:Cholangiocarcinoma / Q000188:drug therapy*; D016503:Drug Delivery Systems; D006801:Humans; D008297:Male; D008819:Mice, Nude; D010743:Phospholipids / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D017207:Rats, Sprague-Dawley; D016896:Treatment Outcome; D014315:Triterpenes / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D010743:Phospholipids; D014315:Triterpenes; C041246:cucurbitacin B; D001599:Berberine
keywords: Antitumor efficacy; Cholangiocarcinoma; Pharmacokinetic modeling of biliary excretion; Phospholipid complex