Nano DDS Technologies for the Gene and siRNA Delivery Based on the Intracellular Environment-responsive Lipid like Materials

Abstract

Development of a nanotechnology to control an intracellular trafficking is highly desired as a gene/siRNA medication. In this review, we will first summarize our previous progress in quantitative comparison and underlying mechanisms of the intracellular trafficking between adenovirus vector and plasmid DNA (pDNA) transfected by non-viral vector (cationic lipoplex). Our analysis revealed that the poor post-nuclear delivery event, as well as nuclear delivery process are key processes to be overcome. Especially, less effective transcription and translation is most likely due to the electrostatic interaction of cationic component in lipoplex with pDNA cargo and mRNA, respectively. To overcome these drawback, we have developed a liposomal nanoparticle (LNP) that are formed using SS-cleavable and pH-activated lipid-like materials (ssPalm). The LNPs prepared using ssPalm are designed to destabilize the endosomal membrane in response to the acidic pH in endosomes, and be spontaneously collapsed in responsive to the reducing environment in the cytoplasm, aided by proton-sponge units (tertiary amines) and a cleavage unit (disulfide bonding), respectively. A series of ssPalm-containing particles were prepared containing myristic acid (ssPalmM), retinoic acid (ssPalmA) and α-tocopherol (ssPalmE) as hydrophobic scaffolds. In this review, we will summarize our recent achievement using this particle for the pDNA/siRNA delivery.