Biodegradable Sucrose Ester-Based Cationic Lipids as Novel Vectors for Efficient and Safe Delivery of IGF-1R siRNA

The key to the success of siRNA therapy depends on the use of siRNA delivery agents that effectively penetrate tumor cells and simultaneously protect siRNA from RNase attacks. Sucrose esters (SEs) are found to have tremendous potential applications in siRNA delivery because of their biocompatibility and low toxicity. However, the esterification of sucrose yields complex mixtures that greatly limit their progress in this field. We synthesized a series of novel sucrose monoester-based cationic lipids (SECLs) by using 1 & PRIME;,4,6 & PRIME;trichlorogalactosucrose (TGS) to achieve monoesterification of sucrose. SECL-based liposomes formed from these lipids and colipids [dioleoylphosphatidylethanolamine (DOPE) or cholesterol (Chol)] could effectively condense genes into nanocomplexes, which exhibited significantly higher uptake rates and gene silencing efficiency than 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP) liposome. Furthermore, SECL-based liposomes containing cholesterol-mediated IGF-1R siRNA delivery could inhibit tumor growth by the downregulation of Bcl-2 and the upregulation of Bax. Most importantly, these liposomes displayed low cytotoxicity in vitro and in vivo because they could be degraded under tumor acidic pH environments. Our study establishes a novel method for the synthesis of SEs from TGS and demonstrates the applicability of SECLs for gene delivery with the potential for clinical therapy. [GRAPHICS]