title: Preparation and antitumor evaluation of self-assembling oleanolic acid-loaded Pluronic P105/d-α-tocopheryl polyethylene glycol succinate mixed micelles for non-small-cell lung cancer treatment.
abstract: Oleanolic acid (OA) is a triterpenoid found in various fruits and vegetables and used in traditional Chinese medicine. OA plays a crucial role in the treatment of several cancers, but poor water solubility, low permeability, and significant efflux have limited its widespread clinical use. Vitamin E-d-α-tocopheryl polyethylene glycol succinate (vitamin E-TPGS) and Pluronic P105 were used to improve the solubility and permeability and to decrease the efflux of OA. OA-loaded mixed micelles were prepared by ethanol thin-film hydration. The physicochemical properties of the micelles, including zeta potential, morphology, particle size, solubility, drug loading, and drug entrapment efficiency were characterized. OA release from micelles was slower than that from the free drug system. OA uptake by A549 non-small-cell lung cancer (NSCLC) cells was enhanced by the micelles. A tumor model was established by injecting A549 cells into nude mice. In vivo imaging showed that OA-micelles could accumulate in the tumors of nude mice. Additionally, smaller tumor size and increased expression of pro-apoptotic proteins were observed in OA-micelle-treated mice, indicating that OA-micelles are more effective than free OA in treating cancer. In vitro experiments were performed using two NSCLC cell lines (A549 and PC-9). Cytotoxicity evaluations showed that the half-maximal inhibitory concentrations of free OA and OA-micelles were 36.8±4.8 and 20.9±3.7 μM, respectively, in A549 cells and 82.7±7.8 and 56.7±4.7 μM, respectively, in PC-9 cells. Apoptosis assays revealed that the apoptotic rate of OA-micelle-treated A549 and PC-9 cells was higher than that of cells treated with the same concentration of free OA. Wound healing and transwell assays showed that migration and invasion were significantly suppressed in OA-micelle-treated cells. Immunofluorescence and Western blot analyses confirmed that the epithelial-mesenchymal transition was reversed in OA-micelle-treated cells. Mixed micelles are a promising nano-drug delivery system for lung cancer treatment.
authors.affiliation: Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine; Key Laboratory of New Drug Delivery System of Chinese Materia Medica, Jiangsu Province Academy of Chinese Medicine, Nanjing, Jiangsu; College of Pharmacy, Anhui University of Chinese Medicine, Hefei, Anhui.
authors.forename: Hao
authors.initials: H
authors.lastname: Wu
authors.affiliation: Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine; Key Laboratory of New Drug Delivery System of Chinese Materia Medica, Jiangsu Province Academy of Chinese Medicine, Nanjing, Jiangsu.
authors.forename: Qingxiang
authors.initials: Q
authors.lastname: Zhong
authors.affiliation: Laboratory Animal Center, Jiangsu Province Academy of Chinese Medicine, Nanjing, Jiangsu.
authors.forename: Rongling
authors.initials: R
authors.lastname: Zhong
authors.affiliation: Laboratory Animal Center, Jiangsu Province Academy of Chinese Medicine, Nanjing, Jiangsu.
authors.forename: Houcai
authors.initials: H
authors.lastname: Huang
authors.affiliation: Laboratory Animal Center, Jiangsu Province Academy of Chinese Medicine, Nanjing, Jiangsu.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Xia
authors.affiliation: Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine; College of Chemistry and Chemical Engineering, Huangshan University, Huangshan, Anhui, People's Republic of China.
authors.forename: Zhongcheng
authors.initials: Z
authors.lastname: Ke
authors.affiliation: Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine.
authors.forename: Zhenhai
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine; Key Laboratory of New Drug Delivery System of Chinese Materia Medica, Jiangsu Province Academy of Chinese Medicine, Nanjing, Jiangsu.
authors.forename: Jie
authors.initials: J
authors.lastname: Song
authors.affiliation: Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine; Key Laboratory of New Drug Delivery System of Chinese Materia Medica, Jiangsu Province Academy of Chinese Medicine, Nanjing, Jiangsu; College of Pharmacy, Anhui University of Chinese Medicine, Hefei, Anhui.
authors.forename: Xiaobin
authors.initials: X
authors.lastname: Jia
mesh_terms: D000072283:A549 Cells; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000473:pathology; D002465:Cell Movement / Q000187:drug effects; D004337:Drug Carriers / Q000737:chemistry; D065546:Drug Liberation; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D007275:Injections, Intravenous; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008819:Mice, Nude; D008823:Micelles; D009828:Oleanolic Acid / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D010316:Particle Size; D020442:Poloxamer / Q000737:chemistry*; D014810:Vitamin E / Q000494:pharmacology / Q000627:therapeutic use*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D004337:Drug Carriers; D008823:Micelles; D020442:Poloxamer; D014810:Vitamin E; D009828:Oleanolic Acid; C519610:pluronic P105; C014225:tocophersolan
keywords: NSCLC; Pluronic P105; oleanolic acid; polymer–drug conjugate; vitamin E-TPGS