Version 2 2024-02-23, 18:12Version 2 2024-02-23, 18:12
Version 1 2024-02-21, 16:08Version 1 2024-02-21, 16:08
journal contribution
posted on 2024-02-23, 18:12authored byDaniel Eckhardt, Enrico F. Semeraro, Jessica Steigenberger, Johannes Schnur, Louma Kalie, Ulrich Massing, Georg Pabst, Heiko Heerklotz
A better molecular
understanding of the temperature-triggered drug
release from lysolipid-based thermosensitive liposomes (LTSLs) is
needed to overcome the recent setbacks in developing this important
drug delivery system. Enhanced drug release was previously rationalized
in terms of detergent-like effects of the lysolipid monostearyl lysophosphatidylcholine
(MSPC), stabilizing local membrane defects upon LTSL lipid melting.
This is highly surprising and here referred to as the ‘lysolipid
paradox,’ because detergents usually induce the opposite effectthey
cause leakage upon freezing, not melting. Here, we aim at better answers
to (i) why lysolipid does not compromise drug retention upon storage
of LTSLs in the gel phase, (ii) how lysolipids can enhance drug release
from LTSLs upon lipid melting, and (iii) why LTSLs typically anneal
after some time so that not all drug gets released. To this end, we
studied the phase transitions of mixtures of dipalmitoylphosphatidylcholine
(DPPC) and MSPC by a combination of differential scanning and pressure
perturbation calorimetry and identified the phase structures with
small- and wide-angle X-ray scattering (SAXS and WAXS). The key result
is that LTSLs, which contain the standard amount of 10 mol % MSPC,
are at a eutectic point when they release their cargo upon melting
at about 41 °C. The eutectic present below 41 °C consists
of a MSPC-depleted gel phase as well as small domains of a hydrocarbon
chain interdigitated gel phase containing some 30 mol % MSPC. In these
interdigitated domains, the lysolipid is stored safely without compromising
membrane integrity. At the eutectic temperature, both the MSPC-depleted
bilayer and interdigitated MSPC-rich domains melt at once to fluid
bilayers, respectively. Intact, fluid membranes tolerate much less
MSPC than interdigitated domainswhere the latter have melted,
the high local MSPC content causes transient pores. These pores allow
for fast drug release. However, these pores disappear, and the membrane
seals again as the MSPC distributes more evenly over the membrane
so that its local concentration decreases below the pore-stabilizing
threshold. We provide a pseudobinary phase diagram of the DPPC–MSPC
system and structural and volumetric data for the interdigitated phase.