Colloids and Surfaces A: Physicochemical and Engineering Aspects
Influence of surfactant and lipid chain length on the solubilisation of phosphatidylcholine vesicles by micelles comprised of polyoxyethylene sorbitan monoesters
Introduction
The effect of the addition of a micelle-forming surfactant on the integrity of phospholipid vesicles has been widely investigated for a number of reasons, including to achieve an understanding of the ability of such surfactants to solubilise biological membranes [1], to allow the reconstitution of functional membranes [2], and to aid in the preparation of phospholipid vesicles [3], [4], [5]. It is generally found that, at low levels of added surfactant, i.e. at low surfactant:phospholipid molar ratios, the vesicles remain intact, although they may appear to slightly swell and/or fuse, while at high surfactant:phospholipid ratios mixed micelles are the predominate species. The pathway and mechanism of transformation from the vesicular suspension to a mixed micellar solution has been successfully explained for wide range of different lipid/surfactant mixtures [8], [9], [10], [11], [12], [13], [14], [15] using the ‘three-stage model’ proposed by Lichtenberg et al. [7]. In this model, vesicles are solubilised by micelle-forming surfactants via an intermediate stage during which both vesicles and micelles co-exist.
The Lichtenberg model however has not always been observed to adequately describe the solubilisation of phosphatidylcholine vesicles by nonionic surfactants, including polyoxyethylene-containing surfactants [6], [16], because of very wide range of possible aggregates that mixtures of phospholipid/nonionic surfactants can form in solution [16]. The description of the vesicle–micelle transition is further complicated by the dependence upon temperature of the phase behaviour of the non-ionic surfactants. For example, it has been observed that mixtures of some phospholipid/non-ionic surfactants can exhibit a reversible vesicle-mixed micelle transformation upon altering temperature [6], [16], [17]. Although this thermally-induced transformation has only been observed in mixed systems containing non-ionic surfactant, it seems to be a general feature of such systems and has been seen with mixtures of phospholipid with either polyoxyethylene-containing surfactants or sugar surfactants such as octylglucoside [17].
Surprisingly, very little work has been performed investigating the solubilisation of phospholipid vesicles by micelle-forming polyoxyethylene sorbitan monoester surfactants (Fig. 1), this is despite the use of the micelles formed by a number of these surfactants as vehicles for the intravenous delivery of water-insoluble drugs. Yet an understanding of the interaction of these surfactants with model biological membranes, such as those present in phospholipid vesicles, may aid in the rationale selection of surfactants for the purposes of drug delivery.
In the present study the solubilisation, by high concentrations of polyoxyethylene sorbitan monoesters, of vesicles prepared by phophatidylcholines (PC) of differing acyl chain length has been investigated at 25 °C. The experimental temperature is well below the cloud point (or lower consulate temperature (i.e. >100 °C)) of the Tween surfactants ensuring that the solubilisation behaviour observed in the present study was not complicated by the close proximity of a phase boundary. The molar ratio of surfactant to phospholipid used in the present study is high (generally in the range of 3.33:1 to 30:1) for two reasons. Firstly, preliminary experiments suggested that, under the conditions of the study, high molar ratios of surfactant to phospholipids were required for complete solubilisation of the vesicles by the surfactant micelles. Secondly, it is necessary, in order to use Tween surfactants as micellar drug delivery vehicles, to administer relatively high concentrations of surfactant.
Section snippets
Materials
Dimyristoyl-, distearoyl- and dioleoylphosphatidylcholine (DMPC, DSPC and DOPC, respectively), purity >99%, were purchased from Avanti (US). Dipalmitoylphosphatidylcholine (DPPC), >99% purity, was obtained from Sigma Chemicals (UK) as were the polyoxyethylene (20) sorbitan monoesters, Tween 20 (polyoxyethylene (20) sorbitan monolaurate), 9:1 mixtures of polyoxyethylene (20) sorbitan monopalmitate and monostearate (Tween 40), 1:1 mixtures of polyoxyethylene (20) sorbitan monopalmitate and
Results
All the phospholipids investigated formed vesicles using the thin film hydration method described. Fig. 2 shows the freeze fracture electron micrograph of vesicles prepared from DSPC. As can be clearly seen from Fig. 2, the vesicles formed by DSPC were (predominately, if not exclusively) unilamellar in nature. It can be noted that the faceted nature of these vesicles is due to the high phase transition (55.3 °C) of DSPC [20]. As with DPSC, the electron micrographs obtained for the other vesicle
Discussion
In order to explain the phase behaviour of the mixed surfactant systems such as studied here, it is common to rationalize the results in terms of the critical packing parameter (CPP) of the constituent amphiphiles [23], [24]. The CPP of an amphiphile is defined by v/aolc, where v is the volume of hydrocarbon chains (generally assumed to be fluid and incompressible), ao is the optimal head group area and lc the critical chain length which corresponds to the maximum effective length that the
Conclusion
The effect of the addition of Tween surfactant to phospholipid vesicles appears to depend on both the length and degree of unsaturation of the acyl chain of the Tween surfactant and the length and degree of unsaturation of the diacyl chains of the phospholipid. The relatively short acyl chains of DMPC mean that the vesicles formed by this lipid are easily solubilised by the Tween surfactants, with the exception of Tween 60, which contains the longest acyl chains. Lengthening the diacyl chains
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