title: Spontaneous Vesiculation and pH-Induced Disassembly of a Lysosomotropic Detergent: Impacts on Lysosomotropism and Lysosomal Delivery.
abstract: Lysosomotropic detergents (LDs) selectively rupture lysosomal membranes through mechanisms that have yet to be characterized. A consensus view, currently, holds that LDs, which are weakly basic, diffuse across cellular membranes as monomers in an uncharged state, and via protonation in the acidic lysosomal compartment, they become trapped, accumulate, and subsequently solubilize the membrane and induce lysosomal membrane permeabilization. Here we demonstrate that the lysosomotropic detergent O-methyl-serine dodecylamide hydrochloride (MSDH) spontaneously assembles into vesicles at, and above, cytosolic pH, and that the vesicles disassemble as the pH reaches 6.4 or lower. The aggregation commences at concentrations below the range of those used in cell studies. Assembly and disassembly of the vesicles was studied via dynamic light scattering, zeta potential measurements, cryo-TEM, and fluorescence correlation spectroscopy and was found to be reversible via control of the pH. Aggregation of MSDH into closed vesicles under cytosolic conditions is at variance with the commonly held view of LD behavior, and we propose that endocytotic pathways should be considered as possible routes of LD entry into lysosomes. We further demonstrate that MSDH vesicles can be loaded with fluorophores via a solution transition from low to high pH, for subsequent release when the pH is lowered again. The ability to encapsulate molecular cargo into MSDH vesicles together with its ability to disaggregate at low pH and to permeabilize the lysosomal membrane presents an intriguing possibility to use MSDH as a delivery system.
authors.affiliation: Experimental Pathology, Department of Clinical and Experimental Medicine, Linköping, University , SE-581 85 Linköping, Sweden.
authors.forename: Ana M
authors.initials: AM
authors.lastname: Villamil Giraldo
authors.forename: Timmy
authors.initials: T
authors.lastname: Fyrner
authors.affiliation: Royal Institute of Technology, Department of Applied Physics, Experimental Biomolecular Physics, Scilifelab , 171 65 Solna, Sweden.
authors.forename: Stefan
authors.initials: S
authors.lastname: Wennmalm
authors.affiliation: Departments of Biomedical Engineering and Materials Science & Engineering, University of California , Davis, California 95616, United States.
authors.forename: Atul N
authors.initials: AN
authors.lastname: Parikh
authors.affiliation: Experimental Pathology, Department of Clinical and Experimental Medicine, Linköping, University , SE-581 85 Linköping, Sweden.
authors.forename: Karin
authors.initials: K
authors.lastname: Öllinger
authors.forename: Thomas
authors.identifier: 0000-0002-1639-5735
authors.initials: T
authors.lastname: Ederth
mesh_terms: D000577:Amides / Q000737:chemistry*; D017209:Apoptosis; D003902:Detergents / Q000737:chemistry*; D007425:Intracellular Membranes / Q000737:chemistry*; D008247:Lysosomes / Q000737:chemistry*; D012694:Serine / Q000031:analogs & derivatives* / Q000737:chemistry
chemical_list: D000577:Amides; D003902:Detergents; C407126:O-methyl-serine dodecylamide hydrochloride; D012694:Serine