title: Improved intervention of atherosclerosis and cardiac hypertrophy through biodegradable polymer-encapsulated delivery of glycosphingolipid inhibitor.
abstract: D-Threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (D-PDMP), a glycosphingolipid synthesis inhibitor, holds promise for the treatment of atherosclerosis and cardiac hypertrophy but rapid in vivo clearance has severely hindered translation to the clinic. To overcome this impediment, we used a materials-based delivery strategy wherein D-PDMP was encapsulated within a biodegradable polymer composed of poly ethylene glycol (PEG) and sebacic acid (SA). PEG-SA was formulated into nanoparticles that were doped with (125)I-labeled PEG to allow in vivo bio-distribution and release kinetics of D-PDMP to be determined by using γ-scintigraphy and subsequently, by mass spectrometry. Polymer-encapsulation increased the residence time of D-PDMP in the body of a treated mouse from less than one hour to at least four hours (and up to 48 h or longer). This substantially increased in vivo longevity provided by polymer encapsulation resulted in an order of magnitude gain in efficacy for interfering with atherosclerosis and cardiac hypertrophy in apoE-/- mice fed a high fat and high cholesterol (HFHC) diet. These results establish that D-PDMP encapsulated in a biodegradable polymer provides a superior mode of delivery compared to unconjugated D-PDMP by way of increased gastrointestinal absorption and increased residence time thus providing this otherwise rapidly cleared compound with therapeutic relevance in interfering with atherosclerosis, cardiac hypertrophy, and probably other diseases associated with the deleterious effects of abnormally high glycosphingolipid biosynthesis or deficient catabolism.
authors.affiliation: Department of Pediatrics, Johns Hopkins University, Baltimore, MD 21287, USA.
authors.forename: S
authors.initials: S
authors.lastname: Mishra
authors.affiliation: Department of Medicine, Johns Hopkins University, Baltimore, MD 21287, USA.|Faculty of Medicine and Health Sciences, Macquarie University, Sydney, Australia.
authors.forename: D
authors.initials: D
authors.lastname: Bedja
authors.affiliation: Department of Pediatrics, Johns Hopkins University, Baltimore, MD 21287, USA.
authors.forename: C
authors.initials: C
authors.lastname: Amuzie
authors.affiliation: Department of Radiology, Johns Hopkins University, Baltimore, MD 21287, USA.
authors.forename: C A
authors.initials: CA
authors.lastname: Foss
authors.affiliation: Department of Radiology, Johns Hopkins University, Baltimore, MD 21287, USA.
authors.forename: M G
authors.initials: MG
authors.lastname: Pomper
authors.affiliation: Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD 21231, USA.
authors.forename: R
authors.initials: R
authors.lastname: Bhattacharya
authors.affiliation: Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD 21231, USA.
authors.forename: K J
authors.initials: KJ
authors.lastname: Yarema
authors.affiliation: Department of Pediatrics, Johns Hopkins University, Baltimore, MD 21287, USA.
authors.forename: S
authors.initials: S
authors.lastname: Chatterjee
mesh_terms: D000818:Animals; D001018:Aortic Diseases / Q000097:blood / Q000188:drug therapy / Q000517:prevention & control; D001057:Apolipoproteins E / Q000172:deficiency; D050197:Atherosclerosis / Q000097:blood / Q000188:drug therapy* / Q000517:prevention & control; D002214:Capsules; D006332:Cardiomegaly / Q000097:blood / Q000188:drug therapy*; D002791:Cholesterol, Dietary / Q000633:toxicity; D003652:Decanoic Acids; D003692:Delayed-Action Preparations; D003998:Dicarboxylic Acids; D004036:Diet, Atherogenic; D004353:Drug Evaluation, Preclinical; D006352:Heart Ventricles / Q000473:pathology; D008658:Inactivation, Metabolic; D007457:Iodine Radioisotopes / Q000032:analysis; D008055:Lipids / Q000097:blood; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015394:Molecular Structure; D009025:Morpholines / Q000008:administration & dosage* / Q000493:pharmacokinetics; D053758:Nanoparticles / Q000008:administration & dosage; D011092:Polyethylene Glycols; D014018:Tissue Distribution; D059289:Vascular Stiffness / Q000187:drug effects
chemical_list: D001057:Apolipoproteins E; D002214:Capsules; D002791:Cholesterol, Dietary; D003652:Decanoic Acids; D003692:Delayed-Action Preparations; D003998:Dicarboxylic Acids; D007457:Iodine Radioisotopes; D008055:Lipids; D009025:Morpholines; D011092:Polyethylene Glycols; C033110:RV 538; C011107:sebacic acid
keywords: Atherosclerosis; Biomaterials-based drug delivery; Cardiac hypertrophy; Glycosphingolipids