Novel thermosensitive small multilamellar lipid nanoparticles with promising release characteristics made by dual centrifugation

Thermosensitive liposomes (TSLs) have great potential for the selective delivery of cytostatic drugs to the tumor site with greatly reduced side effects. Here we report the discovery and characterization of new thermosensitive small multilamellar lipid nanoparticles (tSMLPs) with unusually high temperature selectivity. Furthermore, the temperature-dependent release of the fluorescent marker calcein from tSMLPs is enhanced by human serum albumin. tSMLPs can easily be prepared through dual centrifugation (DC) at very high lipid concentrations using dipalmitoyl and distearoyl phosphatidylcholine (DPPC, DSPC) and the phospholipid dipalmitoyl-sn-glycero-phosphatidyldiglycerol (DPPG₂). The new particles have a hydrodynamic diameter of about 175 nm and a narrow size distribution (PDI 0.02). tSMLPs consist of multiple lipid membranes, which become increasingly closer packed towards the particle center, and have no visible aqueous core. The particles are highly stable due to strong hydrogen bond-based membrane interactions mediated by DPPG₂. tSMLPs can be used as carriers for water-soluble drugs (EE 25 %) entrapped within the interlamellar spaces. Based on biophysical (DSC, DLS and ITC) and morphological (cryo-EM) studies, a hypothesis is presented to explain the structural basis underlying the high temperature selectivity, as well as the unusual morphology of the new thermosensitive lipid nanoparticles.