Phospholipid bicelles revisited - Examining their properties for topical drug delivery

While phospholipid bicelles have long been known as membrane models, the current work focuses on their potential application as topical drug delivery systems. For this, a systematic investigation of bicelles was performed to define the conditions required to maintain the small size and disk-shaped morphology that are favorable for skin penetrating properties. Bicelles consisting of 1,2- dimyristoyl-sn-glycero-3-phosphocholine (DMPC, C14) and 1,2-dihexanoyl-sn-glycero-3-PC (C6) were used as starting point. PCs bearing acyl chains with either 6 or 7 carbon atoms (C6, C7) could both be mixed with C14, 1,2-dipalmitoyl-sn-glycero-3-PC (C16) or 1-palmitoyl-2-oleoyl-sn-glycero-3-PC (C16/C18:1) to fulfill the desired conditions. Size, dynamic properties, and morphology were analyzed by DLS, ¹H NMR diffusion ordered spectroscopy, and cryo-TEM. Stable bicelles were formed at low q-values (<2) and total phospholipid concentrations on average above 15 mM. The phase transition temperatures T_m of C14 and C16 in bicelles were found to be 12.2 ± 1.1 °C and 19.6 ± 1.1 °C in combination with C6, and 10.6 ± 4.4 °C and 22.4 ± 2.1 °C, respectively, when combined with C7. These values, determined by ¹H NMR spectroscopy, were significantly reduced in bicelles compared to their one-component counterparts. The capability of C14/C16-C6/C7 bicelles for encapsulating two water-insoluble porphyrinic photosensitizers (PSs), m-THPP and chlorin e4 (Ce4) in their non-aggregated form, was demonstrated by ¹H NMR. The phase transition profile of bicelles with reduced T_m was largely retained in the presence of encapsulated PSs, except for C14-C6 where T_m went back up. Initial skin penetration experiments demonstrated the ability of bicelles to deliver the PS into the superficial epidermal layer of porcine skin as visualized by fluorescence microscopy. The data underline the high potential of bicelles as topical delivery systems and provide guidelines for preparing bicelles with controlled properties important for predicting and optimizing their skin interaction.