title: Suppression of Remodeling Behaviors with Arachidonic Acid Modification for Enhanced in vivo Antiatherogenic Efficacies of Lovastatin-loaded Discoidal Recombinant High Density Lipoprotein.
abstract: OBJECTIVE
  A series of in vitro evaluation in our previous studies had proved that arachidonic acid (AA) modification could suppress the remodeling behaviors of lovastatin-loaded discoidal reconstituted high density lipoprotein (LT-d-rHDL) by restraining the reactivity with lecithin cholesterol acyltransferase (LCAT) for reducing undesired drug leakage. This study focuses on the investigation of AA-modified LT-d-rHDL (AA-LT-d-rHDL) in atherosclerotic New Zealand White (NZW) rabbit models to explore whether AA modification could enhance drug targeting delivery and improve antiatherogenic efficacies in vivo.
  
  
  METHODS
  After pharmacokinetics of AA-LT-d-rHDL modified with different AA amount were investigated in atherosclerotic NZW rabbits, atherosclerotic lesions targeting property was assessed by ex vivo imaging of aortic tree and drug distribution. Furthermore, their antiatherogenic efficacies were elaborately evaluated and compared by typical biochemical indices.
  
  
  RESULTS
  With AA modification amount augmenting, circulation time of AA-LT-d-rHDL was prolonged, and drug accumulation in the target locus was increased, eventually the significant appreciation in antiatherogenic efficacies were further supported by lower level of bad cholesterol, decreased atherosclerotic lesions areas and mean intima-media thickness (MIT), markedly attenuated matrix metalloproteinase-9 (MMP-9) protein expression and macrophage infiltration.
  
  
  CONCLUSIONS
  This proof-of-concept study demonstrated that AA-LT-d-rHDL could enhance drug accumulation in atherosclerotic lesion and impede atherosclerosis progression more effectively.
authors.affiliation: Department of Pharmaceutics, China Pharmaceutical University, No.24, Tongjia Lane, Nanjing, 210009, People's Republic of China.
authors.forename: Hongliang
authors.initials: H
authors.lastname: He
authors.affiliation: Department of Pharmaceutics, China Pharmaceutical University, No.24, Tongjia Lane, Nanjing, 210009, People's Republic of China.
authors.forename: Mengyuan
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Department of Pharmaceutics, China Pharmaceutical University, No.24, Tongjia Lane, Nanjing, 210009, People's Republic of China.
authors.forename: Lisha
authors.initials: L
authors.lastname: Liu
authors.affiliation: Department of Pharmaceutics, China Pharmaceutical University, No.24, Tongjia Lane, Nanjing, 210009, People's Republic of China.
authors.forename: Shuangshuang
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Department of Pharmaceutics, China Pharmaceutical University, No.24, Tongjia Lane, Nanjing, 210009, People's Republic of China. jianpingliu1293@163.com.
authors.forename: Jianping
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Pharmaceutics, China Pharmaceutical University, No.24, Tongjia Lane, Nanjing, 210009, People's Republic of China. jianpingliu1293@163.com.
authors.forename: Wenli
authors.initials: W
authors.lastname: Zhang
mesh_terms: D000818:Animals; D016718:Arachidonic Acid / Q000737:chemistry*; D050197:Atherosclerosis / Q000188:drug therapy* / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism; D004337:Drug Carriers / Q000737:chemistry; D016503:Drug Delivery Systems / Q000379:methods; D008075:Lipoproteins, HDL / Q000378:metabolism*; D008148:Lovastatin / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D007862:Phosphatidylcholine-Sterol O-Acyltransferase / Q000378:metabolism; D011817:Rabbits
chemical_list: D004337:Drug Carriers; D008075:Lipoproteins, HDL; D016718:Arachidonic Acid; D002784:Cholesterol; D008148:Lovastatin; D007862:Phosphatidylcholine-Sterol O-Acyltransferase; D020780:Matrix Metalloproteinase 9
keywords: LCAT; antiatherogenic efficacies; arachidonic acid modified d-rHDL; drug leakage; remodeling behaviors