Hidetaka Akita
Hokkaido University, Japan
Title: Particle formed by ssPalm as a nanoDDS platform for the genes and nucleic acids
Biography
Biography: Hidetaka Akita
Abstract
Recently, we design a nanoparticle which is neutral at physiological (cytoplasmic) pH to avoid mRNA interactions, and is degradable for the effective release of DNA or nucleic acids in response to the cytoplasmic environment. The key molecule to realize this concept is an ionizable lipid-like material; we refer to as SS-cleavable Proton-Activated Lipid-like Material (ssPalm). This molecule mounts dual sensing motifs that can respond to the intracellular environment; positively charged tertiary amines responsible for an acidic compartment (endosome/lysosome) for membrane destabilization, and disulfide bonding that can be cleaved in reducing environment (cytosol). The liposomal nanoparticle formed with ssPalm (LNPssPalm) was stable for at least 24 h in serum. The dynamic flow of LNPssPalm, with evidence for no aggregate formation and rapid liver accumulation was verified after the intravenous administration by in vivo intravital real-time confocal laser scanning microscopy. Moreover, the long-lasting gene expression (>2 weeks) in the liver without no production of the inflammatory cytokines were conferred. Furthermore, the surface modification of the LNPssPalm with PEG prolonged the blood circulation, and resulted in the successful gene expression in tumor tissue. As a 2nd generation of ssPalms were developed, in those fat-soluble vitamins such as vitamin A or vitamin E was used as a hydrophobic scaffold. Selection of the adequate hydrophobic scaffold and further molecular tuning in tertiary amines resulted in the development of the hepatic siRNA delivery system. Collectively, ssPalm is one of the promising platforms as a carrier for genes and siRNA.