I am looking for a lipid composition that allows for the preperation of thermoresponsive liposomes; ideally with a tunable phase transition temperature in a temperature range between 37 and 42°C. These liposomes will be loaded with N-Acetyl-D-Glucosamin (GlcNAc), which should only be released, when the temperature exceeds the phase transition temperature.
Does anyone have expirence with this or a similar case? I tried a composition of DPPC and DOTAP, however, these liposomes started leaking even below their phase transition temperature - I attributed this to interactions between the lipids and the GlcNAc, since I observed precipitates.
Thanks for your help :)
The zwitterionic 1,2-dipalmitoyl-sn-3-glycero-phosphatidylcholine (DPPC) and the corresponding phosphatidylglycerol (DPPG), which is anionic in physiological pH range, undergo chain melting phase transition (the so-called main transition) at temperature , T_m, just below 42 °C. Both these phospholipids can also undergo so-called pre-transition at T= T_p, some 6 degrees below T_m, under suitable conditions; the latter transition is nearly ten times more sensitive to perturbations (such as ionic strength or headgroup ionisation change) than T_m, owing to its much lower pretransition enthalpy compared with the main transition enthalpy. (see, e.g., figure 3 in Chemistry and Physics of Lipids, 57 (1991) 293--307). In principle, either of the two lipids or their mixture, could therefore serve your purpose. If you would like to achieve lowe transition temperatures, you could admixing dimyristoyl-PC and/or PG, with T_m ~ 24 °C, to DPPC and/or DPPG; these lipids mix reasonably well and will have correspondingly lower overall chain melting (and pretransition) temperatures.
You should always keep in mind, however, that plasma or other biological fluids components typically lower T_m (and in case T_p) of most phospholipid bilayers. T_m can be therefore as low as 38 °C and T_p typically disappears under in vivo conditions, dependent on such components adsorbtion to lipid bilayer surfaces (see, e.g., studio biophysica 138 (1990) 57-70. You should also mind the high DPPG- solubility in polar solvents and also the unusually strong salt dependence of phosphatidylglycerols, esp. at low ionic strengths (see, e.g., Adv Colloid Interf Sci 88 (2000) 79-97; Proc. Natl. Acad. Sci. 96 (1999) 14312–14317; Biochemistry 33 (1994) 9477–9488.) Furthermore, the amino-sugar, which you would like to encapsulate into the selected lipid vesicles, might interact with the proposed (and other kind of) phospolipid bilayers, too, at least if given sufficient time for that (see Ber. Bunsen Ges. 92 (1988) 953-961).
Finally, you should know that DPPC and DPPG, like all other synthetic phospholipids, are rather pricy.
In short, you are addressing a relatively complicated problem.
Thank you very much for this indeed very detailed answer. It will help me a lot.
If you plan to / need to admix other kind of molecules to the mixtures suggested in my answer, you should also (pre)check their effect(s) on bilayer properties, including T_m (and, in case, T_p). Whereas bilayer surface 'coating' with PEG, or some other suitable polymer, is indeed likely to modify in concentration dependent manner the adsorption of relatively large molecules, such as proteins, similar effects will be much smaller for any much smaller adsorbent. You should moreover keep in mind that a PEG layer modifies not just interfacial repulsion but also interfacial polarity profile, and hence influences protonation constants (pK_a) of PG, and any other ionizable, molecule with (a) titratable group(s) within the profile range. My most general advice is therefore: "To understand properly and to cope well with biomolecular constructs you should try to feel like the involved biomolecules".
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