Induction of asymmetry in vesicles
First Claim
1. An asymmetric liposome having an outer bilayer which comprises an ionizable lipid or an ionizable protein wherein the outer bilayer has an asymmetric distribution of the ionizable lipid or ionizable protein within the two monolayers which comprise the outer bilayer, said asymmetric distribution induced by a transmembrane concentration gradient wherein the gradient is a pH gradient.
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Abstract
Methods are described for controlling the transbilayer distribution of ionizable lipids and proteins in vesicles. Control of the ion gradient of the exterior bathing medium in relation to that of the interior entrapped aqueous compartment of the vesicles induces migration of ionizable lipids or proteins to one or the other of the monolayers comprising the bilayer. This can result in an asymmetric distribution of the ionizable lipid or ionizable protein. The basic ionizable lipids, such as stearylamine and sphingosine, are sequestered into the inner monolayer when the liposome interior is acidic relative to the liposome exterior. Conversely, acidic ionizable lipids such as oleic acid and stearic acid are sequestered into the inner monolayer when the liposome interior is basic relative to the liposome exterior bathing solution. Likewise, phospholipids such as phosphatidylglycerol, phosphatidylinositol, and cardiolipin may also be sequestered into the inner monolayer in response to a relatively acidic exterior medium. Such vesicles may contain bioactive agents and may be administered to mammals including humans.
217 Citations
28 Claims
- 1. An asymmetric liposome having an outer bilayer which comprises an ionizable lipid or an ionizable protein wherein the outer bilayer has an asymmetric distribution of the ionizable lipid or ionizable protein within the two monolayers which comprise the outer bilayer, said asymmetric distribution induced by a transmembrane concentration gradient wherein the gradient is a pH gradient.
- 20. An asymmetric liposome wherein the liposome is a large unilamellar liposome or a liposome having two or more bilayers, the liposome having an outer bilayer which comprises an ionizable lipid or an ionizable protein wherein the outer bilayer has asymmetric distribution of the ionizable lipid or ionizable protein within the two monolayers which comprise the outer bilayer.
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28. An asymmetric liposome having an outer bilayer which comprises an ionizable lipid or an ionizable protein wherein the outer bilayer has an asymmetric distrubution of the ionizable lipid or ionizable protein within the two monolayers which comprise the outer bilayer, made by a transmembrane concentration gradient process comprising the steps of:
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(a) preparing liposomes with an internal buffer at a first pH; and (b) exposing the liposomes of step (a) to an external aqueous buffer at a second, relatively acidic or basic pH, to obtain asymmetric liposomes.
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Specification