title: Association of daunorubicin to a lipid nanoemulsion that binds to low-density lipoprotein receptors enhances the antitumour action and decreases the toxicity of the drug in melanoma-bearing mice.
abstract: OBJECTIVE
  To test the toxicity and antitumoral activity of the compound N-oleyl-daunorubicin (oDNR) with a cholesterol-rich nanoemulsion (LDE) formulation.
  
  
  METHODS
  LDE-oDNR was prepared by high-pressure homogenisation of lipid mixtures. B16F10 melanoma cells and NIH/3T3 fibroblasts were used for cytotoxicity tests. The maximum tolerated dose (MTD) of both commercial and LDE-oDNR was determined in mice, and melanoma-bearing mice were used for the antitumoral activity tests.
  
  
  RESULTS
  CC50 for LDE-oDNR and DNR in melanoma cells were 200 μm and 15 μm, respectively, but LDE-oDNR was less toxic against fibroblasts than DNR. MTD for LDE-oDNR was 65-fold higher than commercial DNR. In tumour-bearing mice, LDE-oDNR (7.5 μmol/kg) reduced tumour growth by 59 ± 2%, whereas the reduction by DNR was only 23 ± 2%. LDE-oDNR increased survival rates (P < 0.05), which was not achieved by DNR treatment. The number of mice with metastasis was only 30% in LDE-oDNR-treated mice, compared with 82% under DNR treatment. By flow cytometry, there were 9% viable cells in tumours of animals treated with LDE-oDNR compared with 27% in DNR-treated animals. Less haematological toxicity was observed in LDE-oDNR-treated mice.
  
  
  CONCLUSIONS
  Compared with DNR, LDE-oDNR improved tumour growth inhibition and survival rates with pronouncedly less toxicity, and thus may become a new tool for cancer treatment.
authors.affiliation: Lipid Metabolism Laboratory, Heart Institute of the Medical School Hospital, University of São Paulo, São Paulo, Brazil.
authors.forename: Thaís C
authors.initials: TC
authors.lastname: Contente
authors.forename: Iara F
authors.initials: IF
authors.lastname: Kretzer
authors.forename: Fabiola B
authors.initials: FB
authors.lastname: Filippin-Monteiro
authors.forename: Durvanei A
authors.initials: DA
authors.lastname: Maria
authors.forename: Raul C
authors.initials: RC
authors.lastname: Maranhão
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000627:therapeutic use* / Q000633:toxicity; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002784:Cholesterol / Q000737:chemistry*; D003630:Daunorubicin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use* / Q000633:toxicity; D004337:Drug Carriers / Q000737:chemistry*; D004355:Drug Stability; D004655:Emulsions; D008297:Male; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008810:Mice, Inbred C57BL; D015394:Molecular Structure; D049329:Nanostructures / Q000737:chemistry*; D009368:Neoplasm Transplantation; D009829:Oleic Acids / Q000008:administration & dosage / Q000627:therapeutic use* / Q000633:toxicity; D010316:Particle Size; D011485:Protein Binding; D011973:Receptors, LDL / Q000378:metabolism*; D023382:Toxicity Tests, Acute
chemical_list: D000903:Antibiotics, Antineoplastic; D004337:Drug Carriers; D004655:Emulsions; C000599289:N-oleyl-daunorubicin; D009829:Oleic Acids; D011973:Receptors, LDL; D002784:Cholesterol; D003630:Daunorubicin
keywords: cancer treatment; daunorubicin; drug delivery; low-density lipoprotein receptors; nanoparticles