Lipothioureas as Lipids for Gene Transfection: A Review

Pharmaceuticals

Marie Breton¹  Jeanne Leblond²  Isabelle Tranchant³  Daniel Scherman⁴  Michel Bessodes⁴  Jean Herscovici⁴ 

[1] UMR 8203, Laboratoire de Vectorologie et Thérapeutiques Anticancéreuses, Université Paris-Sud, 91405 Orsay, CNRS Institut Gustave Roussy, 94805 Villejuif, France;Faculté de Pharmacie, Université de Montréal, CP 6128, Succ Centre-Ville, Montréal, QC, H3C 3J7, Canada;Commissariat à l'Energie Atomique, Service d'Ingénierie des Protéines, 152, CE-Saclay, 91191 Gif sur Yvette, France;UMR 8151 CNRS, U1022 INSERM, Unité de Pharmacologie Chimique et Génétique et d'Imagerie, Université Paris Descartes, Sorbonne Paris Cité, Chimie-ParisTech, 4 avenue de l'observatoire, 75006 Paris, France

关键词: lipothiourea;    thiourea lipids;    DNA;    lipoplexes;    transfection;    gene therapy;   

DOI  :  10.3390/ph4101381

来源: mdpi

【 摘 要 】

Non-viral gene therapy requires innovative strategies to achieve higher transfection efficacy. A few years ago, our group proposed bioinspired lipids whose interaction with DNA was not based on ionic interactions, but on hydrogen bonds. We thus developed lipids bearing a thiourea head which allowed an interaction with DNA phosphates through hydrogen bonds. After a proof of concept with a lipid bearing three thiourea functions, a molecular and cellular screening was performed by varying all parts of the lipids: the hydrophobic anchor, the spacer, the linker, and the thiourea head. Two lipothiourea-based structures were identified as highly efficient in vitro transfecting agents. The lipothioureas were shown to reduce non specific interactions with cell membranes and deliver their DNA content intracellularly more efficiently, as compared to cationic lipoplexes. These lipids could deliver siRNA efficiently and allowed specific cell targeting in vitro. In vivo, thiourea lipoplexes presented a longer retention time in the blood and less accumulation in the lungs after an intravenous injection in mice. They also induced luciferase gene expression in muscle and tumor after local administration in mice. Therefore, these novel lipoplexes represent an excellent alternative to cationic lipoplexes as transfecting agents. In this review we will focus on the structure activity studies that permitted the identification of the two most efficient thiourea lipids.

【 授权许可】

CC BY   
© 2011 by the authors; licensee MDPI, Basel, Switzerland.