Title:
Development of intracellular environment-responsive material as a nanoDDS platform: Analysis, control of the intracellular trafficking and beyond…
Speaker:
Hidetaka Akita
Graduate School of Pharmaceutical Sciences, Chiba University
Abstract:
A category of biomedicine is now expanding from low-molecular drugs to the recombinant protein, antibody, and nucleic acids (i.e. siRNA, mRNA and plasmid DNA). While the gene therapy approach has faced technical and/or regulatory impediments, a large number of clinical trials are still ongoing worldwide. One crucial success is the first approval of the Glybera® (UniQure) by the European Medicinal Agency (EMA) as a first gene-based medication
Gene delivery efficacy is rate-limited by the multiple processes (i.e. cellular uptake, endosomal escape, cytoplasmic transport and nuclear delivery). Adequate design to overcome these barriers is a minimum requirement. Our quantitative and mechanism-based information on differences in transfection efficiency between viral and artificial cationic vectors revealed that post-nuclear delivery processes (i.e. transcription and translation) predominantly contributed to the poor transfection efficacy in artificial ones in dividing cells. In other words, the process of the post-organelle delivery process (intra-organelle disposition) should be taken into the consideration.
To overcome this dilemma, 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). In this presentation, I will show an design and application of ssPalm as a tool for the delivery of DNA and nucleic acids.
References:
1. Akita H*, Noguchi Y, Hatakeyama H, Sato Y, Tange K, Nakai Y, Harashima H* Molecular tuning of a vitamin E-scaffold pH-sensitive and reductive cleavable lipid-like material for accelerated in vivo hepatic siRNA delivery. ACS Biomater Sci Eng. 1(9): 834-844 (2015)
2. Akita H*, Ishiba R, Togashi R, Tange K, Nakai Y, Hatakeyama H, Harashima H* A neutral lipid envelope-type nanoparticle composed of a pH-activated and vitamin E-scaffold lipid-like material as a platform for a gene carrier targeting renal cell carcinoma. J Control Release. 200:97-105 (2015)
3. Ukawa M, Akita H* (Equal contribution to 1st author）, Hayashi Y, Ishiba R, Tange K, Arai M, Kubo K, Higuchi Y, Shimizu K, Konishi S, Hashida M, Harashima H*. Neutralized nanoparticle composed of SS-cleavable and pH-activated lipid-like material as a long-lasting and liver-specific gene delivery system. Adv Healthc Mater. 3(8):1222-9 (2014)
4. Tanaka H, Akita H* (Equal contribution to 1st author）, Ishiba R, Tange K, Arai M, Kubo K, Harashima H* Neutral biodegradable lipid-envelope-type nanoparticle using vitamin A-Scaffold for nuclear targeting of plasmid DNA. Biomaterials. 35(5):1755-61 (2014)
5. Akita H*, Ishiba R, Hatakeyama H, Tanaka H, Sato Y, Tange K, Arai M, Kubo K, Harashima H* A neutral envelope-type nanoparticle containing pH-responsive and SS-cleavable lipid-like material as a carrier for plasmid DNA. Adv Healthc Mater. 2(8):1120-5 (2013)
