title: Liposomal co-delivery of omacetaxine mepesuccinate and doxorubicin for synergistic potentiation of antitumor activity.
abstract: OBJECTIVE
  Anticancer chemotherapy usually involves the administration of several anticancer drugs that differ in their action mechanisms. Here, we aimed to test whether the combination of omacetaxine mepesuccinate (OMT) and doxorubicin (DOX) could show synergism, and whether the liposomal co-delivery of these two drugs could enhance their antitumor effects in cervical carcinoma model.
  
  
  METHODS
  OMT-loaded liposomes (OL) were prepared by loading the drug in the lipid bilayers. OL were then electrostatically complexed with DOX, yielding double-loaded liposomes (DOL). DOX-loaded liposomes (DL) were formulated by electrostatic interaction with negatively charged empty liposomes (EL). The combination index (CI) values were calculated to evaluate the synergism of two drugs. In vitro antitumor effects against HeLa cells were measured using CCK-8, calcein staining, and crystal violet staining. In vivo antitumor effects of various liposomes were tested using HeLa cell-bearing mice.
  
  
  RESULTS
  Combination of DOX and OMT had ratio-dependent synergistic activities, with very strong synergism observed at a molar ratio of 4:1 (DOX:OMT). The sizes of EL, DL, OL, and DOL did not significantly differ, but the zeta potentials of DL and DOL were slightly higher than those of OL and EL. In vitro, DOL showed higher antitumor activity than OL, DL or EL in cervical carcinoma HeLa cells. In vivo, unlike other liposomes, DOL reduced the tumor growths by 98.6% and 97.3% relative to the untreated control on day 15 and 25 after the cessation of treatment, respectively.
  
  
  CONCLUSIONS
  These results suggest that liposomal co-delivery of DOX and OMT could synergistically potentiate antitumor effects.
authors.affiliation: College of Pharmacy Research Institute of Pharmaceutical Sciences, Seoul National University, Daehak-dong, Gwanak-gu, Seoul, 151-742, Korea.
authors.forename: Gayong
authors.initials: G
authors.lastname: Shim
authors.forename: Sangbin
authors.initials: S
authors.lastname: Lee
authors.forename: Junhyeok
authors.initials: J
authors.lastname: Choi
authors.forename: Soondong
authors.initials: S
authors.lastname: Lee
authors.forename: Chan-Wha
authors.initials: CW
authors.lastname: Kim
authors.forename: Yu-Kyoung
authors.initials: YK
authors.lastname: Oh
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000008:administration & dosage / Q000031:analogs & derivatives*; D004337:Drug Carriers / Q000008:administration & dosage*; D016503:Drug Delivery Systems / Q000379:methods*; D004357:Drug Synergism; D005260:Female; D006248:Harringtonines / Q000008:administration & dosage*; D006367:HeLa Cells; D000077863:Homoharringtonine; D006801:Humans; D008081:Liposomes; D051379:Mice; D008819:Mice, Nude; D011092:Polyethylene Glycols / Q000008:administration & dosage; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: D000970:Antineoplastic Agents; D004337:Drug Carriers; D006248:Harringtonines; D008081:Liposomes; C506643:liposomal doxorubicin; D011092:Polyethylene Glycols; D000077863:Homoharringtonine; D004317:Doxorubicin