Cyclodextrin-based facial amphiphiles: assessing the impact of the hydrophilic-lipophilic balance in the self-assembly, DNA complexation and gene delivery capabilities.

Exhaustive structure-efficacy relationship studies on nonviral gene delivery systems are often hampered by the ill-defined or polydisperse nature of the formulations. Facial amphiphiles based on rigid cage-type molecular scaffolds offer unique possibilities towards these studies. Taking advantage of regioselective functionalization schemes, we have synthesized a library of cationic cyclodextrin (CD) derivatives combining a range of hydrophilic and lipophilic domains. We have scrutinized how the hydrophilic-lipophilic balance (HLB) around the CD scaffold determines their self-assembly capabilities and the DNA binding and release abilities of the corresponding CD : DNA nanocomplexes (CDplexes). These features have been ultimately correlated with their capabilities to deliver a reporter luciferase-encoding pDNA into COS-7 cells. The ensemble of results demonstrates that fine tuning of the HLB is critical to induce compaction of DNA by the CD-based facial amphiphiles into transfection-productive CDplexes.

Implementing the "catch-and-release" concept into a simple method for regioselective cyclodextrin modification.

Differentiation of specific positions in axial-symmetrical cyclodextrins (CDs), exhibiting a dense display of identical functional groups, is challenging. A novel strategy toward this goal that exploits a solid matrix to display the complementary reagent functionalities sufficiently far from each other to prevent CDs from reacting through more than one site is reported. Using a "catch-and-release" process based on the Staudinger reaction, the utility of this concept to easily produce complex CD functionalization patterns in one pot and without any purification step is demonstrated.