title: Delivery of daunorubicin to cancer cells with decreased toxicity by association with a lipidic nanoemulsion that binds to LDL receptors.
abstract: A lipidic nanoemulsion termed LDE concentrates in neoplastic cells after injection into the bloodstream and thus can be used as a drug carrier to tumour sites. The chemotherapeutic agent daunorubicin associates poorly with LDE; the aim of this study was to clarify whether the derivatization of daunorubicin by the attachment of an oleyl group increases the association with LDE, and to test the cytotoxicity and animal toxicity of the new preparation. The association of oleyl-daunorubicin (oDNR) to LDE showed high yield (93 +/- 2% and 84 +/- 4% at 1:10 and 1:5 drug:lipid mass, respectively) and was stable for at least 20 days. Association with oDNR increased the LDE particle diameter from 42 +/- 4 nm to 75 +/- 6 nm. Cytotoxicity of LDE-oDNR was reduced two-fold in HL-60 and K-562 cell lines, fourteen-fold in B16 cells and nine-fold in L1210 cells when compared with commercial daunorubicin. When tested in mice, LDE-oDNR showed remarkable reduced toxicity (maximum tolerated dose > 253 micromol kg(-1), compared with <3 micromol kg(-1) for commercial daunorubicin). At high doses, the cardiac tissue of LDE-oDNR-treated animals had much smaller structural lesions than with commercial daunorubicin. LDE-oDNR is therefore a promising new preparation that may offer superior tolerability compared with commercial daunorubicin.
authors.affiliation: Lipid Metabolism and Pathology Laboratories, Heart Institute (InCor), University of São Paulo Medical School, São Paulo, Brazil.
authors.forename: Raquel S
authors.initials: RS
authors.lastname: Teixeira
authors.forename: Claudete J
authors.initials: CJ
authors.lastname: Valduga
authors.forename: Luis A
authors.initials: LA
authors.lastname: Benvenutti
authors.forename: Shirley
authors.initials: S
authors.lastname: Schreier
authors.forename: Raul C
authors.initials: RC
authors.lastname: Maranhão
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002626:Chemistry, Pharmaceutical / Q000379:methods; D003630:Daunorubicin / Q000008:administration & dosage / Q000737:chemistry* / Q000378:metabolism; D016503:Drug Delivery Systems / Q000379:methods; D004355:Drug Stability; D004655:Emulsions / Q000737:chemistry / Q000378:metabolism; D018922:HL-60 Cells; D006321:Heart / Q000187:drug effects; D006801:Humans; D020014:K562 Cells; D053208:Kaplan-Meier Estimate; D008055:Lipids / Q000737:chemistry*; D051379:Mice; D008854:Microscopy, Electron; D009206:Myocardium / Q000378:metabolism / Q000648:ultrastructure; D053758:Nanoparticles / Q000008:administration & dosage / Q000737:chemistry*; D010316:Particle Size; D011973:Receptors, LDL / Q000378:metabolism*; D013678:Technology, Pharmaceutical / Q000379:methods; D023382:Toxicity Tests, Acute / Q000379:methods
chemical_list: D000903:Antibiotics, Antineoplastic; D004655:Emulsions; D008055:Lipids; D011973:Receptors, LDL; D003630:Daunorubicin