title: PEGylated-nanoliposomal clusterin for amyloidogenic light chain-induced endothelial dysfunction.
abstract: Light chain (AL) amyloidosis is a disease associated with significant morbidity and mortality arising from multi-organ injury induced by amyloidogenic light chain proteins (LC). There is no available treatment to reverse the toxicity of LC. We previously showed that chaperone glycoprotein clusterin (CLU) and nanoliposomes (NL), separately, restore human microvascular endothelial function impaired by LC. In this work, we aim to prepare PEGylated-nanoliposomal clusterin (NL-CLU) formulations that could allow combined benefit against LC while potentially enabling efficient delivery to microvascular tissue, and test efficacy on human arteriole endothelial function. NL-CLU was prepared by a conjugation reaction between the carboxylated surface of NL and the primary amines of the CLU protein. NL were made of phosphatidylcholine (PC), cholesterol (Chol) and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[carboxy(polyethylene glycol)-2000] (DSPE-PEG 2000 carboxylic acid) at 70:25:5 mol%. The protective effect of NL-CLU was tested by measuring the dilation response to acetylcholine and papaverine in human adipose arterioles exposed to LC. LC treatment significantly reduced the dilation response to acetylcholine and papaverine; co-treatment of LC with PEGylated-nanoliposomal CLU or free CLU restored the dilator response. NL-CLU is a feasible and promising approach to reverse LC-induced endothelial damage.
authors.affiliation: a Department of Pharmaceutical Sciences , College of Pharmacy-Glendale, Midwestern University , AZ , USA.|b Nanomedicine Center of Excellence in Translation Cancer Research , Glendale , AZ , USA.
authors.forename: Diana
authors.initials: D
authors.lastname: Guzman-Villanueva
authors.affiliation: c Phoenix Veterans Affairs Health Care System , AZ , USA.|d University of Arizona College of Medicine-Phoenix , AZ , USA.
authors.forename: Raymond Q
authors.initials: RQ
authors.lastname: Migrino
authors.affiliation: c Phoenix Veterans Affairs Health Care System , AZ , USA.
authors.forename: Seth
authors.initials: S
authors.lastname: Truran
authors.affiliation: c Phoenix Veterans Affairs Health Care System , AZ , USA.
authors.forename: Nina
authors.initials: N
authors.lastname: Karamanova
authors.affiliation: c Phoenix Veterans Affairs Health Care System , AZ , USA.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Franco
authors.affiliation: c Phoenix Veterans Affairs Health Care System , AZ , USA.
authors.forename: Camelia
authors.initials: C
authors.lastname: Burciu
authors.affiliation: e Department of Ophthalmology and Visual Sciences , Case Western Reserve University , OH , USA.
authors.forename: Subhadip
authors.initials: S
authors.lastname: Senapati
authors.affiliation: f Biodesign Institute, Arizona State University , AZ , USA , and.
authors.forename: Dobrin
authors.initials: D
authors.lastname: Nedelkov
authors.affiliation: g Department of Medicine , Medical College of Wisconsin , Milwaukee , WI , USA.
authors.forename: Parameswaran
authors.initials: P
authors.lastname: Hari
authors.affiliation: a Department of Pharmaceutical Sciences , College of Pharmacy-Glendale, Midwestern University , AZ , USA.|b Nanomedicine Center of Excellence in Translation Cancer Research , Glendale , AZ , USA.
authors.forename: Volkmar
authors.initials: V
authors.lastname: Weissig
mesh_terms: D000109:Acetylcholine / Q000737:chemistry; D058227:Amyloidogenic Proteins / Q000378:metabolism*; D000686:Amyloidosis / Q000188:drug therapy*; D001160:Arterioles / Q000187:drug effects / Q000378:metabolism; D002784:Cholesterol / Q000737:chemistry; D051152:Clusterin / Q000008:administration & dosage* / Q000737:chemistry; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D008081:Liposomes / Q000737:chemistry*; D053758:Nanoparticles / Q000737:chemistry*; D010208:Papaverine / Q000737:chemistry; D010316:Particle Size; D010713:Phosphatidylcholines / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry; D014664:Vasodilation / Q000187:drug effects
chemical_list: D058227:Amyloidogenic Proteins; D051152:Clusterin; D008081:Liposomes; D010713:Phosphatidylcholines; D011092:Polyethylene Glycols; D002784:Cholesterol; D010208:Papaverine; C000595210:polyethylene glycol 2000; D000109:Acetylcholine
keywords: Amyloidosis; PEGylation; clusterin; light chain; liposomes