title: Effect of an oral astaxanthin prodrug (CDX-085) on lipoprotein levels and progression of atherosclerosis in LDLR(-/-) and ApoE(-/-) mice.
abstract: Oxidative stress and inflammation are key promoters of atherosclerosis and myocardial damage. When orally administered, the novel astaxanthin prodrug CDX-085 delivers high levels of the xanthophyll antioxidant astaxanthin that protects LDL from oxidation and reduces primary thrombosis. In this study, we analyzed whether delivery of astaxanthin from administration of the CDX-085 prodrug reduces plasma lipoprotein levels and the progression of atherosclerosis in low-density lipoprotein receptor negative (LDLR(-/-)) and apolipoprotein E deficient (ApoE(-/-)) mice.
  
  
  METHODS
  Relative circulating levels of astaxanthin derived from CDX-085 administration compared to administration of pure astaxanthin was initially evaluated in a canine model. In mouse Study #1, 16 wild-type and 16 LDLR(-/-) mice on 0.5% cholesterol diet supplemented with either 0.0%, 0.08%, 0.2% and 0.4% CDX-085 were used to assess plasma levels and lipoprotein biodistribution measured by FPLC after 4 weeks treatment. In Study #2, 36 male LDLR(-/-) mice were randomized to a 0.5% cholesterol chow diet (CHOW group, n=12) or 0.5% cholesterol chow fortified with 0.08% CDX-085 (n=12) or 0.5% cholesterol chow with 0.4% CDX-085 (n=12) for 12 weeks. In Study #3, 34 male ApoE(-/-) mice were randomized in the same fashion as the Study #2 and fed similar diets for 9 weeks.
  
  
  RESULTS
  CDX-085 administration was shown to result in significantly higher levels of circulating astaxanthin (p<0.001 ANOVA) over a 72 h period compared to pure, non-esterified astaxanthin in a single-dose pharmacokinetic study in beagles. In Study #1, plasma astaxanthin levels were 5-9-fold higher in LDLR(-/-) mice compared to wild-type mice. Astaxanthin was highly distributed among all lipoprotein fractions, generally reflecting cholesterol content of lipoproteins. In Study #2, administration of CDX-085 resulted in significantly lower total cholesterol levels (528±68 mg/dL vs. 550±67 mg/dL vs. 602±80 mg/dL, p=0.047) and aortic arch atherosclerosis (9.0±4.2% vs. 9.8±3.5% vs. 13.2±3.6%, p=0.023) in the 0.4% CDX-085 group compared to the 0.08% CDX-085 and CHOW groups, respectively. In ApoE(-/-) mice, a 72% reduction in triglycerides in the 0.4% CDX-085 group and 50% reduction in the 0.08% CDX-085 groups was noted compared to CHOW group (final levels 17±11 mg/dL vs. 30±15 mg/dL vs. 60±32 mg/dL, respectively, p=0.001).
  
  
  CONCLUSIONS
  Oral administration of the novel astaxanthin prodrug CDX-085 shows that it distributes among lipoproteins. CDX-085 lowers total cholesterol and aortic arch atherosclerosis in LDLR(-/-) mice and triglyceride levels in ApoE(-/-) mice and shows promise for further evaluation in human studies.
authors.affiliation: Division of Cardiovascular Diseases, University of California San Diego, La Jolla, CA 92093, USA.
authors.forename: Sung Kee
authors.initials: SK
authors.lastname: Ryu
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: King
authors.forename: Kazutoshi
authors.initials: K
authors.lastname: Fujioka
authors.forename: Jennifer
authors.initials: J
authors.lastname: Pattison
authors.forename: Fredrick J
authors.initials: FJ
authors.lastname: Pashkow
authors.forename: Sotirios
authors.initials: S
authors.lastname: Tsimikas
mesh_terms: D000818:Animals; D001018:Aortic Diseases / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency*; D050197:Atherosclerosis / Q000473:pathology / Q000503:physiopathology*; D002784:Cholesterol / Q000097:blood; D004285:Dogs; D008074:Lipoproteins / Q000097:blood; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011355:Prodrugs / Q000494:pharmacology; D011973:Receptors, LDL / Q000172:deficiency*; D014280:Triglycerides / Q000097:blood; D024341:Xanthophylls / Q000097:blood / Q000494:pharmacology*
chemical_list: D001057:Apolipoproteins E; C574298:CDV-085; D008074:Lipoproteins; D011355:Prodrugs; D011973:Receptors, LDL; D014280:Triglycerides; D024341:Xanthophylls; C005948:astaxanthine; D002784:Cholesterol