title: A bufadienolide-loaded submicron emulsion for oral administration: stability, antitumor efficacy and toxicity.
abstract: The purpose of this study was to develop an alternative submicron emulsion containing three bufadienolides for oral administration and evaluate its preclinical stability, efficacy, and toxicity. The bufadienolide-loaded oral submicron emulsion (BU-OE) was prepared by high-pressure homogenization. The storage stability, in vitro cytotoxicity, in vivo antitumor efficacy, acute toxicity, and long-term toxicity of BU-OE were investigated in detail to evaluate the formulation. The stability study suggested that BU-OE was stable at room temperature and could be stored for at least 18 months at 6±2 °C. The cytotoxicity test revealed that BU-OE had marked cytotoxic activities against cancer cells, but no evident inhibitory effects on normal cells. Likewise, BU-OE exhibited significant antitumor efficacy against Hep G2, HCT-8, and EC9706 cell lines and a slight inhibitory effect on BGC 803 cell line in nude mice, while comparable antitumor activity with fluorouracil injection. The LD50 of BU-OE in mice was 29.4 mg/kg (male) and 22.8 mg/kg (female), respectively. As for the long-term toxicity, BU-OE showed no apparent toxic effects except minor cardiotoxic effects which were reversible. In conclusion, submicron emulsion is a suitable delivery system for oral administration of bufadienolides, with satisfactory stability, superior antitumor efficacy and low toxicity.
authors.affiliation: Department of Pharmaceutics, Shenyang Pharmaceutical University, Shenyang, China.
authors.forename: Wanqiu
authors.initials: W
authors.lastname: Li
authors.affiliation: School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Xia
authors.initials: X
authors.lastname: Lin
authors.affiliation: Department of Pharmaceutics, Shenyang Pharmaceutical University, Shenyang, China.
authors.forename: Zhenhua
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Department of Pharmaceutics, Shenyang Pharmaceutical University, Shenyang, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Pharmaceutics, Shenyang Pharmaceutical University, Shenyang, China.
authors.forename: Tianyang
authors.initials: T
authors.lastname: Ren
authors.affiliation: Department of Pharmaceutics, Shenyang Pharmaceutical University, Shenyang, China.
authors.forename: Fengming
authors.initials: F
authors.lastname: Qu
authors.affiliation: Department of Pharmaceutics, Shenyang Pharmaceutical University, Shenyang, China.
authors.forename: Yanjiao
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Pharmacy Department, Second Hospital of Dalian Medical University, Dalian, China. Electronic address: zn-dl@163.com.
authors.forename: Ning
authors.initials: N
authors.lastname: Zhang
authors.affiliation: Department of Pharmaceutics, Shenyang Pharmaceutical University, Shenyang, China. Electronic address: tanglab@126.com.
authors.forename: Xing
authors.initials: X
authors.lastname: Tang
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use / Q000633:toxicity; D002018:Bufanolides / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use / Q000633:toxicity; D002453:Cell Cycle / Q000187:drug effects; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004355:Drug Stability; D004655:Emulsions; D005260:Female; D006801:Humans; D007928:Lethal Dose 50; D008297:Male; D008807:Mice, Inbred BALB C; D008813:Mice, Inbred ICR; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology; D017207:Rats, Sprague-Dawley; D012995:Solubility; D023382:Toxicity Tests, Acute; D059551:Toxicity Tests, Subacute; D016896:Treatment Outcome; D047368:Tumor Burden / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D002018:Bufanolides; D004655:Emulsions
keywords: Antitumor efficacy; Bufadienolides; Oral submicron emulsion; Stability; Toxicity