title: Development and modeling of arsenic-trioxide-loaded thermosensitive liposomes for anticancer drug delivery.
abstract: In this article, a novel delivery system for the anticancer drug, arsenic trioxide (ATO), is characterized. The release of ATO from DPPC liposomes with MPPC lysolipid incorporated into the bilayer was measured. Upon heating the liposomes to 37°C, there was a 15-25% release over 24 hours. The ATO release from the DPPC and DPPC:MPPC (5%) systems leveled off after 10 hours at 37°C, whereas the DPPC:MPPC (10%) liposomes continue to release ATO over the 24-hour time span. Upon heating the liposomes rapidly to 42°C, the release rate was substantially increased. The systems containing lysolipids exhibited a very rapid release of a significant amount of arsenic in the first hour. In the first hour, the DPPC:MPPC (5%) liposomes released 40% of the arsenic and the DPPC:MPPC (10%) liposomes released 55% of the arsenic. Arsenic release from pure DPPC liposomes was comparable at 37 and 42°C, indicating that the presence of a lysolipid is necessary for a significant enhancement of the release rate. A coarse-grained molecular dynamics (CGMD) model was used to investigate the enhanced permeability of lysolipid-incorporated liposomes and lipid bilayers. The CG liposomes did not form a gel phase when cooled due to the high curvature; however, permeability was still significantly lower below the liquid-to-gel phase-transition temperature. Simulations of flat DPPC:MPPC bilayers revealed that a peak in the permeability did coincide with the phase transition from the gel to LC state when the lysolipid, MPPC, was present. No pores were observed in the simulations, so it is unlikely this was the permeability-enhancing mechanism.
authors.affiliation: Department of Chemistry, Northwestern University, Evanston, Illinois, USA.
authors.forename: Nicolas D
authors.initials: ND
authors.lastname: Winter
authors.forename: Ryan K J
authors.initials: RK
authors.lastname: Murphy
authors.forename: Thomas V
authors.initials: TV
authors.lastname: O'Halloran
authors.forename: George C
authors.initials: GC
authors.lastname: Schatz
mesh_terms: D015060:1,2-Dipalmitoylphosphatidylcholine / Q000737:chemistry; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000378:metabolism* / Q000627:therapeutic use; D002152:Calorimetry, Differential Scanning; D005782:Gels / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008051:Lipid Bilayers / Q000737:chemistry* / Q000378:metabolism; D008081:Liposomes / Q000737:chemistry* / Q000378:metabolism*; D056004:Molecular Dynamics Simulation; D009369:Neoplasms / Q000188:drug therapy; D010087:Oxides / Q000378:metabolism* / Q000627:therapeutic use; D010539:Permeability; D044367:Phase Transition; D010713:Phosphatidylcholines / Q000737:chemistry; D044366:Transition Temperature
chemical_list: D001152:Arsenicals; D005782:Gels; D008051:Lipid Bilayers; D008081:Liposomes; D010087:Oxides; D010713:Phosphatidylcholines; D015060:1,2-Dipalmitoylphosphatidylcholine; C086029:1-myristoyl-2-palmitoyl-sn-glycero-3-phosphocholine; D000077237:Arsenic Trioxide