title: Receptor-targeted liposomal delivery of boron-containing cholesterol mimics for boron neutron capture therapy (BNCT).
abstract: Liposomes have been a main focus of tumor-selective boron delivery strategies in boron neutron capture therapy (BNCT), a binary method for the treatment of cancer that is based on the nuclear reaction between boron atoms and low-energy thermal neutrons. Three novel carboranyl cholesterol derivatives were prepared as lipid bilayer components for the construction of nontargeted and receptor-targeted boronated liposomes for BNCT. A major structural feature of these novel boronated cholesterol mimics is the replacement of the B and the C ring of cholesterol with a carborane cluster. Computational analyses indicated that all three boronated compounds have structural features and physicochemical properties that are very similar to those of cholesterol. One of the synthesized boronated cholesterol mimics was stably incorporated into non-, folate receptor (FR)-, and vascular endothelial growth factor receptor-2 (VEGFR-2)-targeted liposomes. No major differences were found in appearance, size distribution, and lamellarity between conventional dipalmitoylphosphatidylcholine (DPPC)/cholesterol liposomes, nontargeted, and FR-targeted liposomal formulations of this carboranyl cholesterol derivative. FR-targeted boronated liposomes were taken up extensively in FR overexpressing KB cells in vitro, and the uptake was effectively blocked in the presence of free folate. In contrast, a boronated cholesterol mimic incorporated into nontargeted liposomes showed significantly lower cellular uptake. There was no apparent in vitro cytotoxicity in FR overexpressing KB cells and VEGFR-2 overexpressing 293/KDR cells when these were incubated with boronated FR- and (VEGFR-2)-targeted liposomes, respectively, although the former accumulated extensively in KB cells and the latter effectively interacted with VEGFR-2 by causing autophosphorylation and protecting 293/KDR cells from SLT (Shiga-like toxin)-VEGF cytotoxicity.
authors.affiliation: Division of Medicinal Chemistry & Pharmacognosy, The Ohio State University, Columbus, 43210, USA.
authors.forename: B T S
authors.initials: BT
authors.lastname: Thirumamagal
authors.forename: Xiaobin B
authors.initials: XB
authors.lastname: Zhao
authors.forename: Achintya K
authors.initials: AK
authors.lastname: Bandyopadhyaya
authors.forename: Sureshbabu
authors.initials: S
authors.lastname: Naranyanasamy
authors.forename: Jayaseharan
authors.initials: J
authors.lastname: Johnsamuel
authors.forename: Rohit
authors.initials: R
authors.lastname: Tiwari
authors.forename: Danold W
authors.initials: DW
authors.lastname: Golightly
authors.forename: Vimalkumar
authors.initials: V
authors.lastname: Patel
authors.forename: Brian T
authors.initials: BT
authors.lastname: Jehning
authors.forename: Marina V
authors.initials: MV
authors.lastname: Backer
authors.forename: Rolf F
authors.initials: RF
authors.lastname: Barth
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Lee
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Backer
authors.forename: Werner
authors.initials: W
authors.lastname: Tjarks
mesh_terms: D001896:Boron Compounds / Q000737:chemistry / Q000378:metabolism*; D016754:Boron Neutron Capture Therapy / Q000379:methods*; D002460:Cell Line; D002784:Cholesterol / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008081:Liposomes / Q000737:chemistry / Q000378:metabolism*; D008958:Models, Molecular; D015394:Molecular Structure; D009369:Neoplasms / Q000628:therapy; D010316:Particle Size; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism
chemical_list: D001896:Boron Compounds; D008081:Liposomes; D042461:Vascular Endothelial Growth Factor A; D002784:Cholesterol; D040301:Vascular Endothelial Growth Factor Receptor-2