Department of Biochemistry and Molecular Biology, University of British Columbia, 2350 Health Sciences Mall, Vancouver, British Columbia V6T 1Z3, Canada.
Langmuir. 2023 Mar 7;39(9):3185-3193. doi: 10.1021/acs.langmuir.2c02794. Epub 2023 Feb 22.
Liposomes, which consist of bilayer lipids surrounding interior aqueous compartment(s), were first characterized nearly 60 years ago. Remarkably, many fundamental properties of liposomes and their micellar-like "solid core" counterparts (a lipid monolayer surrounding a hydrophobic core) and transitions between these structures remain poorly understood. In this work, we examine the effects of basic variables on the morphology adopted by lipid-based systems produced by rapid mixing of lipids in ethanol with aqueous media. We show that, for lipids such as distearolyphosphatidylcholine (DSPC)-cholesterol mixtures that form bilayer vesicles on hydration, osmotic stress can induce regions of high positive membrane curvature, leading to fusion between unilamellar vesicles to produce bilamellar vesicles. Addition of lyso PC, an "inverted cone"-shaped lipid that supports regions of high positive curvature, can inhibit the formation of these bilamellar vesicles by stabilizing a hemifused intermediate structure. Conversely, the presence of "cone"-shaped lipids such as dioleoylphosphatidylethanolamine (DOPE) that results in negative membrane curvature promotes fusion events subsequent to vesicle formation (during the ethanol dialysis stage), leading to bilamellar and multilamellar systems even in the absence of osmotic stress. Alternatively, the presence of increasing amounts of triolein, a lipid that is insoluble in lipid bilayers, results in increasing internal solid core structures until micellar-like systems with a hydrophobic core of triolein are achieved. These results are interpreted in terms of the intrinsic membrane curvature that bilayer vesicles can stably maintain as well as the ability of bilayer lipids to first form a monolayer around a solid core of hydrophobic material such as triolein and then, as the proportion of bilayer lipids is increased, progressively form bilayer structures that can eventually form a complete bilayer encapsulating both a hydrophobic core and an aqueous compartment. These hybrid intermediate structures may have utility as novel drug delivery systems.
脂质体由双层脂质围绕内部水相组成，最早于近 60 年前被描述。值得注意的是，许多脂质体及其类似胶束的“固体核心”（围绕疏水核心的单层脂质）的基本性质以及这些结构之间的转变仍然知之甚少。在这项工作中，我们研究了基本变量对通过在乙醇中快速混合脂质与水介质产生的基于脂质的系统所采用的形态的影响。我们表明，对于在水合时形成双层囊泡的脂质，如二硬脂酰磷脂酰胆碱（DSPC）-胆固醇混合物，渗透压应激可以诱导高正膜曲率区域，导致单层囊泡融合以产生双层囊泡。添加溶血性磷脂酰胆碱（lyso PC），一种支持高正曲率区域的“倒锥”形脂质，可以通过稳定半融合中间结构来抑制这些双层囊泡的形成。相反，存在二油酰基磷脂酰乙醇胺（DOPE）等“锥”形脂质，导致负膜曲率，促进囊泡形成后（在乙醇透析阶段）的融合事件，导致双层和多层系统的形成，即使在不存在渗透压的情况下也是如此。或者，随着不溶于脂质双层的三油酸甘油酯的含量增加，内部固体核心结构增加，直到形成具有三油酸甘油酯疏水核的类似胶束的系统。这些结果根据双层囊泡可以稳定维持的固有膜曲率以及双层脂质首先在疏水物质（如三油酸甘油酯）的固体核周围形成单层的能力来解释，然后随着双层脂质比例的增加，逐渐形成双层结构，最终形成一个完整的双层，包裹疏水核和水相。这些混合中间结构可能作为新型药物传递系统具有实用性。
