title: Nanomicelle formulation modifies the pharmacokinetic profiles and cardiac toxicity of daunorubicin.
abstract: BACKGROUND
  Treatment with daunorubicin (DNR) in acute myeloid leukemia is moderately effective and associated with significant side effects, including cardiac toxicity. We recently developed a nanomicellar formulation of DNR that specifically targets acute myeloid leukemia stem cells.
  
  
  METHODS
  Pharmacokinetics analysis of free DNR, DNR in nanomicellar formulations was performed in Balb/c mice and Sprague-Dawley rats. Histochemical staining, caspase 3/7, troponin and creatine kinase MB isoenzyme were used to assess toxicity.
  
  
  RESULTS
  Compared with free DNR, the nanomicellar formulations of DNR had less cardiotoxicity as evidenced by milder histopathological changes, lower caspase 3/7 activity in heart tissue (p = 0.002), lower plasma creatine kinase MB isoenzyme (p = 0.002) and troponin concentrations (p = 0.001) postinjection. The area under curve concentration of DNR in micelles increased by 31.9-fold in mice (p < 0.0001) and 22.0-fold higher in rats (p < 0.001).
  
  
  CONCLUSIONS
  Leukemia stem cell-targeting micelles dramatically change the pharmacokinetics and reduce the cardiac toxicity of DNR, which may enable improved DNR-based treatment of acute myeloid leukemia.
authors.affiliation: Division of Hematology & Oncology, Department of Internal Medicine, School of Medicine, University of California, Davis, 4501 X Street, Room 3016, Sacramento, CA 95817, USA.
authors.forename: Hongyong
authors.initials: H
authors.lastname: Zhang
authors.forename: Yuanpei
authors.initials: Y
authors.lastname: Li
authors.forename: Tzu-Yin
authors.initials: TY
authors.lastname: Lin
authors.forename: Kai
authors.initials: K
authors.lastname: Xiao
authors.forename: Ashraf S
authors.initials: AS
authors.lastname: Haddad
authors.forename: Paul T
authors.initials: PT
authors.lastname: Henderson
authors.forename: Brian A
authors.initials: BA
authors.lastname: Jonas
authors.forename: Mingyi
authors.initials: M
authors.lastname: Chen
authors.forename: Wenwu
authors.initials: W
authors.lastname: Xiao
authors.forename: Ruiwu
authors.initials: R
authors.lastname: Liu
authors.forename: Kit S
authors.initials: KS
authors.lastname: Lam
authors.forename: Chong-xian
authors.initials: CX
authors.lastname: Pan
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage* / Q000493:pharmacokinetics* / Q000633:toxicity; D066126:Cardiotoxicity / Q000378:metabolism* / Q000473:pathology*; D020169:Caspases / Q000378:metabolism; D002626:Chemistry, Pharmaceutical; D003630:Daunorubicin / Q000008:administration & dosage* / Q000493:pharmacokinetics* / Q000633:toxicity; D050091:Dendrimers / Q000737:chemistry; D016503:Drug Delivery Systems; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008823:Micelles; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D050997:Nanomedicine; D014411:Neoplastic Stem Cells / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000903:Antibiotics, Antineoplastic; D050091:Dendrimers; D008823:Micelles; D020169:Caspases; D003630:Daunorubicin
keywords: cardiotoxicity; daunorubicin; leukemia stem cells; nanomicelles; pharmacokinetics