Sclareol-stabilized hyaluronanosomes containing gemcitabine hydrochloride for antitumor applications

Liposomes represent pivotal supramolecular drug carriers in cancer therapy, enabling the targeted delivery of therapeutics to specific pathological body compartments. In this study, sclareol (SCL), a cytotoxic and cytostatic labdane-type diterpene isolated from Salvia sclarea, was successfully integrated into liposomal formulations as a structural substitute for cholesterol. To bypass the accelerated blood clearance phenomenon commonly triggered by PEGylation, the liposomes were surface-modified with a hyaluronic acid-dipalmitoylphosphatidylethanolamine (HA-DPPE) derivative. This coating was employed to exploit receptor-mediated endocytosis via CD44 receptors, which are characteristically overexpressed on various tumor cells. Gemcitabine hydrochloride (GEM), a hydrophilic nucleoside-analogue anticancer drug, was actively encapsulated within the aqueous core to achieve a synergistic therapeutic effect. Formulations made up of DPPC and SCL at an 8:2 M ratio demonstrated a hydrodynamic diameter of ∼100 nm. Following the post-insertion of the HA-DPPE copolymer, the nanocarriers showed a Zeta potential of −20 mV. The encapsulation of GEM did not compromise the physico-chemical properties of the nanosystems, preserving their mean sizes and low polydispersity index up to a drug concentration of 2 mg/mL. The evaluation of the drug leakage demonstrated a controlled and sustained release of GEM over 24 h, while the cytotoxicity performed via MTT assays on MCF-7, MCF-10A, MDA-MB468 and CaCo-2 cells revealed that HA-DPPE-coated liposomes significantly enhanced the reduction of cell viability compared to the free form of the active compounds. This increased pharmacological efficacy was correlated with superior cell uptake exerted by the HA-derivative on receptor-expressing cells, rationalizing this nanomedicine for targeted oncological therapy.