Smart hyaluronated micelles to enhance a gemcitabine prodrug efficacy

Self-assembling drug delivery systems have drawn attention over recent decades thanks to their versatility and easy preparation processes. Of the various nanocarriers available, micelles are able to self-assemble from an amphiphilic molecule in an aqueous solution, making them simple to prepare. In this work, 1,2-distearoyl- sn -glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000] (PEG-DSPE) was utilized to prepare lipid-based micelles for the encapsulation of a gemcitabine prodrug, GemC18, with the aim of improving its anticancer activity. Furthermore, an active targeting strategy was achieved by preparing Gem-C18-loaded PEG-DSPE micelles in the presence of a hyaluronic acid (4800 or 14,800 Da) (HA)-phospholipid conjugate (HA-DPPE) to provide actively targeted mixed micelles. This study presents the characterization of the mixed micelles, from basic characteristics (size, PDI, and zeta potential) to complex molecular structure (FESEM, X-ray diffraction, SAXS), and demonstrates that the presence of the HA-conjugate does not alter the physicochemical properties of the PEG-DSPE micelles. The mixed micelles display a size of below 100 nm, a negative zeta potential of −30 mV, and a high encapsulation efficiency (above 90 %). Finally, their preferential uptake, and consequently their cytotoxicity on cancer cell lines that overexpress the HA-specific receptor (CD44), has been assessed and confirmed using competition assays. • Mixed micelles self-assemble and efficiently incorporate GemC18. • A very low amount of HA-phospholipid conjugate is suitable to promote targeting ability. • The presence of GemC18 triggers a sphere-to-elongated shape transition of micelles.