Novel lipidated sorbitol-based molecular transporters for non-viral gene delivery

Abstract

In this study, we investigated the possible use of novel lipidated sorbitol-based transporters as functional devices for the improvement of non-viral gene delivery. These transporters are composed of a sorbitol scaffold bearing 8 guanidine moieties that mimic the arginine residues of well-known cell-penetrating peptides. In addition, the transporters carry different lipid groups to aid DNA condensation and facilitate lipid vesicle-binding. We found that the transporters described in this study have the potential to function as plasmid DNA/siRNA-condensers and surface ligands for the enhancement of cellular uptake of lipid vesicles. Shorter lipid chains were found to be better for condensation, whereas longer chains were superior surface ligands. The differential activity of different cores might be explained by facilitated decondensation of cores prepared with transporters comprised of shorter lipid chains. However, we suggest that there is an optimum value of decondensation to achieve higher transfection activities. The proper use of the transporters presented in this study enabled us to prepare a highly efficient non-viral gene delivery system based on a core-shell structure, in which a condensed DNA core is encapsulated by a lipid envelope. A multifunctional envelope-type nano-device prepared with an optimal surface ligand favorably competes with commonly used transfection systems.

Intrathecal injection of a therapeutic gene-containing polyplex to treat spinal cord injury

“…For example, despite the high efficiency of in vitro and even in vivo gene introduction, LPEI still has a problem of long-term safety mostly due to its non-degradability inside the cells, resulting in the regrettable fact that PEI has never been used for clinical purposes. On the other hand, other non-viral systems, especially lipidbased systems, generally have disadvantages in low efficiency of in vivo gene introduction compared with the remarkably high capacity for cultured cells in some cases, comparable to capacities of viral vectors [48,49]. Indeed, for SCI, there are few reports in animal studies showing sufficient improvement of neural function by introduction of therapeutic molecules, although a considerable number of systems achieved in vitro transgene expression in neural cells such as neurons and astrocytes [50].…”

Mitochondrial Affinity of Guanidine-rich Molecular Transporters Built on Monosaccharide Scaffolds: Stereochemistry and Lipophilicity

“…[7][8][9][10][11][12] These guanidine-rich MTs generally exhibited good uptake properties and displayed rather diverse intracellular organellar and tissue selectivity. A series of G8 molecular transporters based on the sorbitol scaffold showed colocalization with MitoTracker Red in HeLa as well as CD34…”

“…The solution was treated with Ag 2 CO 3 (0.383 g, 1.39 mmol), and stirred at rt for 2 h. The mixture was filtered over a bed of celite and concentrated to give 10 (α,β mixture) as a white foamy solid (1.67 g, quant.). R f 0.2 (EtOAc:n-Hexane = 1:2); (11): To a solution of 7 (1.8 g, 2.6 mmol) in CH 2 Cl 2 (10 mL) at 0 o C, was added dropwise 30% HBr/HOAc (1.5 mL). The mixture was stirred at rt for 6 h, and ice water was added to quench the reaction.…”

Self-Assembled Lipoplexes of Short Interfering RNA (siRNA) Using Spermine-Based Fatty Acid Amide Guanidines: Effect on Gene Silencing Efficiency

“…Guanidines have the extra advantage, being bidentate, of being able to form two hydrogen bonds with negatively charged groups e.g., carboxylates, phosphates or sulfates present on the carbohydrates associated with the cell membrane, and this advantage has been used in vectors e.g., R8, Arg 8 [11,12] to transport cargoes across cell membranes. These characteristics led to the design of many non-viral vectors for DNA and siRNA, varying from cationic lipids incorporating guanidine head-groups [13-15] e.g., AtuFECT [15], to cationic polymers [16,17] and dendrimers [18,19], to carbohydrate derivatives [19,20], and hydrogels of guanidinylated hyaluronic acid [21]. The use of guanidinium-containing lipid based carriers for gene delivery dates back to 1996 where Lehn et al synthesized two guanidinium cholesterol lipids: bis-guanidiniumspermidine-cholesterol (BGSC) and bis-guanidinium-trencholesterol (BGTC), each containing two guanidine groups, which were synthesized and evaluated for their DNA transfection efficiencies in eukaryotic cells (Figure 1) [22] where they were found to be efficient DNA transfecting agents.…”