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Article

Novel Cationic Lipids Incorporating an Acid-Sensitive Acylhydrazone Linker: Synthesis and Transfection Properties

Supporting Info

Abderrahim Aissaoui,^†^‡ Benjamin Martin,^‡^§ Erwan Kan,^§ Noufissa Oudrhiri,^† Michelle Hauchecorne,^† Jean-Pierre Vigneron,^§ Jean-Marie Lehn,^§ and Pierre Lehn*^†

INSERM U458, Hpital Robert Debr, AP-HP, 48 Boulevard Srurier, 75019 Paris, France, and Laboratoire de Chimie des Interactions Molculaires, CNRS UPR 285, Collge de France, 11 Place Marcelin Berthelot, 75005 Paris, France

J. Med. Chem., 2004, 47 (21), pp 5210–5223

DOI: 10.1021/jm0408159

Publication Date (Web): September 4, 2004

†

Hôpital Robert Debré.

‡

Both authors contributed equally.

Laboratoire de Chimie des Interactions Moléculaires.

To whom correspondence should be addressed. Phone: +33(0)140031932. Fax: +33(0)140031903. E-mail: lehn@idf.inserm.fr.

Abstract

Cationic lipid-mediated gene transfection involves uptake of the lipid/DNA complexes via endocytosis, a cellular pathway characterized by a significant drop in pH. Thus, in the present study, we aimed to explore the impact on transfection efficiency of the inclusion of an acid-sensitive acylhydrazone function in the cationic lipid structure. We synthesized and evaluated the transfection properties of a series of four cationic steroid derivatives characterized by an acylhydrazone linkage connecting a guanidinium-based headgroup to a saturated cholestanone or an unsaturated cholest-4-enone hydrophobic domain. Acid-catalyzed hydrolysis was confirmed for all lipids, its rate being highest for those with a cholestanone moiety. The compound bis-guanidinium bis(2-aminoethyl)amine hydrazone (BGBH)-cholest-4-enone was found to mediate efficient gene transfection into various mammalian cell lines in vitro and into the mouse airways in vivo. In vitro transfection studies with BGBH-cholest-4-enone formulations also showed that incorporation of a degradable acylhydrazone bond led to low cytotoxicity and impacted the intracellular trafficking of the lipoplexes. Thus, our work allowed us to identify a cationic lipid structure with an acid-cleavable acylhydrazone linker capable of mediating efficient gene transfection in vitro and in vivo and it thereby provides a basis for further development of related acid-sensitive gene delivery systems.

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