title: Reduction of Atherosclerotic Lesions by the Chemotherapeutic Agent Carmustine Associated to Lipid Nanoparticles.
abstract: OBJECTIVE
  After injection in the bloodstream, a lipid nanoparticle (LDE) resembling low-density lipoprotein (LDL) concentrates in atherosclerotic lesions of cholesterol-fed rabbits. Here, rabbits with atherosclerosis were treated with carmustine, an antiproliferative agent used in cancer chemotherapy, associated to LDE to investigate the effects on the lesions.
  
  
  METHODS
  Twenty-seven male New Zealand rabbits were fed a 1 % cholesterol diet for 8 weeks. After 4 weeks nine animals were treated with intravenous saline solution, nine with intravenous LDE alone, and nine with intravenous LDE-carmustine (4 mg/kg, weekly for 4 weeks).
  
  
  RESULTS
  LDE-carmustine reduced lesion size by 90 % compared to the controls. LDE-carmustine reduced the presence of macrophages, vascular smooth muscle cells, and regulatory T cells in the arterial intima, as well as the presence of matrix metallopeptidase-9, interleukin-1β and TNF-α and lipoprotein receptors, namely LDL-receptor, LDL-related protein-1, scavenger receptor class B member 1. When injected alone, without association to carmustine, LDE was not different from injected saline solution.
  
  
  CONCLUSIONS
  LDE-carmustine treatment resulted in marked reduction of lesion area, of the invasion of the arterial intima by macrophages and vascular smooth muscle cells and pro-inflammatory factors. Therefore, this new formulation shows great potential for therapy of atherosclerotic cardiovascular disease.
authors.affiliation: Heart Institute of the Medical School Hospital, University of São Paulo, São Paulo, SP, Brazil.
authors.forename: Elaine N
authors.initials: EN
authors.lastname: Daminelli
authors.affiliation: Heart Institute of the Medical School Hospital, University of São Paulo, São Paulo, SP, Brazil.
authors.forename: Ana E M
authors.initials: AE
authors.lastname: Martinelli
authors.affiliation: Heart Institute of the Medical School Hospital, University of São Paulo, São Paulo, SP, Brazil.|Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, SP, Brazil.
authors.forename: Adriana
authors.initials: A
authors.lastname: Bulgarelli
authors.affiliation: Heart Institute of the Medical School Hospital, University of São Paulo, São Paulo, SP, Brazil.
authors.forename: Fatima R
authors.initials: FR
authors.lastname: Freitas
authors.affiliation: Heart Institute of the Medical School Hospital, University of São Paulo, São Paulo, SP, Brazil. ramarans@usp.br.|Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, SP, Brazil. ramarans@usp.br.
authors.forename: Raul C
authors.initials: RC
authors.lastname: Maranhão
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D001011:Aorta / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D050197:Atherosclerosis / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002330:Carmustine / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use; D002791:Cholesterol, Dietary / Q000008:administration & dosage; D053583:Interleukin-1beta / Q000378:metabolism; D008055:Lipids / Q000008:administration & dosage* / Q000097:blood / Q000737:chemistry / Q000627:therapeutic use; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000378:metabolism; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry / Q000627:therapeutic use; D011817:Rabbits; D011973:Receptors, LDL / Q000378:metabolism; D051122:Scavenger Receptors, Class B / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D018906:Antineoplastic Agents, Alkylating; D002791:Cholesterol, Dietary; D053583:Interleukin-1beta; C475476:LRP1 protein, human; D008055:Lipids; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D011973:Receptors, LDL; C495124:SCARB1 protein, human; D051122:Scavenger Receptors, Class B; D014409:Tumor Necrosis Factor-alpha; D020780:Matrix Metalloproteinase 9; D002330:Carmustine
keywords: Atherosclerosis treatment; Cholesterol; Drug-targeting; Nanoparticles; Solid lipid particles (SLP)