title: pH-Cleavable Nucleoside Lipids: A New Paradigm for Controlling the Stability of Lipid-Based Delivery Systems.
abstract: Lipid-based delivery systems are an established technology with considerable clinical acceptance and several applications in human. Herein, we report the design, synthesis and evaluation of novel orthoester nucleoside lipids (ONLs) for the modulation of liposome stability. The ONLs contain head groups with 3'-orthoester nucleoside derivatives featuring positive or negative charges. The insertion of the orthoester function in the NL structures allows the formation of pH-sensitive liposomes. ONL-based liposomes can be hydrolyzed to provide nontoxic products, including nucleoside derivatives and hexadecanol. To allow the release to be tunable at different hydrolysis rates, the charge of the polar head structure is modulated, and the head group can be released at a biologically relevant pH. Crucially, when ONLs are mixed with natural phosphocholine lipids (PC), the resultant liposome evolves toward the formation of a hexadecanol/PC lamellar system. Biological evaluation shows that stable nucleic acid lipid particles (SNALPs) formulated with ONLs and siRNAs can effectively enter into tumor cells and release their nucleic acid payload in response to an intracellular acidic environment. This results in a much higher antitumor activity than conventional SNALPs. The ability to use pH-cleavable nucleolipids to control the stability of lipid-based delivery systems represents a promising approach for the intracellular delivery of drug cargos.
authors.affiliation: ARNA laboratory-INSERM U869, Université Bordeaux Segalen, 146 Rue Léo Saignat, 33000, Bordeaux, France.
authors.forename: Khalid
authors.initials: K
authors.lastname: Oumzil
authors.affiliation: ARNA laboratory-INSERM U869, Université Bordeaux Segalen, 146 Rue Léo Saignat, 33000, Bordeaux, France.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Benizri
authors.affiliation: ARNA laboratory-INSERM U869, Université Bordeaux Segalen, 146 Rue Léo Saignat, 33000, Bordeaux, France.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Tonelli
authors.affiliation: ARNA laboratory-INSERM U869, Université Bordeaux Segalen, 146 Rue Léo Saignat, 33000, Bordeaux, France.
authors.forename: Cathy
authors.initials: C
authors.lastname: Staedel
authors.affiliation: ARNA laboratory-INSERM U869, Université Bordeaux Segalen, 146 Rue Léo Saignat, 33000, Bordeaux, France.
authors.forename: Ananda
authors.initials: A
authors.lastname: Appavoo
authors.affiliation: INSERM UMR1068-CNRS UMR725, Institut Paoli-Calmettes, 232 Boulevard Sainte Marguerite, 13273, Marseille, France.|Faculté de Médecine, Aix Marseille Université, 27 Boulevard Jean Moulin, 13385, Marseille, France.
authors.forename: Max
authors.initials: M
authors.lastname: Chaffanet
authors.affiliation: Centre de recherche Paul Pascal/UPR 8641, CNRS-Université Bordeaux, 115 Avenue Dr Schweitzer, 33600, Pessac, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Navailles
authors.affiliation: ARNA laboratory-INSERM U869, Université Bordeaux Segalen, 146 Rue Léo Saignat, 33000, Bordeaux, France. philippe.barthelemy@inserm.fr.
authors.forename: Philippe
authors.initials: P
authors.lastname: Barthélémy
mesh_terms: D016503:Drug Delivery Systems; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008055:Lipids / Q000138:chemical synthesis / Q000737:chemistry*; D008081:Liposomes / Q000138:chemical synthesis / Q000737:chemistry*; D009705:Nucleosides / Q000737:chemistry*
chemical_list: D008055:Lipids; D008081:Liposomes; D009705:Nucleosides
keywords: drug delivery; lipids; nucleosides; pH responsive; small interfering RNA (siRNA)