Reduction-triggered delivery using nucleoside-lipid based carriers possessing a cleavable PEG coating

Abstract

A new non-ionic nucleoside based lipid (DOU-SS-PEG 2000, 5′-PEG 2000-2′,3′-dioleoyluridine) featuring uridine (U) as nucleoside and 2′,3′-dioleyl (DO), as lipid moieties and a poly(ethylene glycol) (PEG) thiolytic cleavable spacer for in vitro delivery of drugs is described. The PEG detachable nucleotide lipid (DOU-SS-PEG 2000) was prepared via a convergent synthesis starting from HS-PEG-OMe and uridine. The reduction-triggered delivery using the PEG detachable nucleoside lipid DOU-SS-PEG 2000 was evaluated on both liposomal and micellar objects. The liposomes were prepared from of a mixture of DOTAU (N-[5′-(2′,3′-dioleoyl)uridine]-N′,N′,N′-trimethylammonium tosylate), the PEG detachable nucleoside lipid DOU-SS-PEG 2000 and DOPE-rhodamine (1,2-dioleoyl- sn-glycero-3-phosphoethanolamine-N-(lissamine rhodamine B sulfonyl ammonium salt) (60/40/0.1), whereas a mixture of 99.9% of DOU-SS-PEG 2000 and 0.1% of DOPE-rhodamine was used to prepare micelles. In addition, the supramolecular systems underwent a reduction-induced morphology transition from a micellar to vesicular states, which was characterized by DLS, zeta potential and TEM. The disulfide bond of the PEG chain was cleaved, by adding a reducing agent such as dithiothréitol (DTT), to expose the cationic surface of the liposome. The internalization of the resulting liposomes was facilitated as shown by the enhanced fluorescence signal observed in ovarian cancer cells (SKOV3) compared to the pegylated liposome. Likewise, when DTT was added to the mixture of cells incubated in the presence of DOU-SS-PEG 2000/DOPE-rhodamine micelle, the fluorescence was observed in almost 100% of the SKOV3 cells.