Abstract: The development of acid degradable linkers that rapidly hydrolyze at endosomal pHs is a central problem in the field of drug delivery. Acid degradable linkages are challenging to develop because of their instability. In this report we present a new acid degradable linker based on an azide-acetal, which rapidly hydrolyzes at endosomal pHs but has exceptional stability at pH 7.4. The azide-acetal linkage hydrolyzes via a two-step mechanism that requires reduction and acid hydrolysis and has a unique combination of stability and rapid triggerable hydrolysis. The azide-acetal has a hydrolysis half-life of days at pH 7.4 and can be conveniently synthesized and incorporated into delivery vectors, however after in situ reduction with DTT it hydrolyzes with a t1/2<15 minutes at pH 6.0. We used the azide-acetal linker to synthesize acid degradable analogs of the lipid components of lipid nanoparticles and demonstrate that these new lipids are significantly better at delivering mRNA to mice than traditional lipids. Lipid nanoparticles containing acid degradable lipids transfected multiple non-liver organs after an intravenous injection and efficiently transfected brain tissue after an intracranial injection. The azide-acetal linkage has the potential to solve the instability problems associated with acid degradable linkers and has numerous applications in drug delivery.
Bio: Dr. Niren Murthy is a professor in the Department of Bioengineering at the University of California at Berkeley. Dr. Murthy’s scientific career has focused on the molecular design and synthesis of new materials for drug delivery and molecular imaging. The Murthy laboratory has been recently focused on developing non-viral delivery vehicles that can deliver mRNA and gene editing enzymes in vivo. The Murthy laboratory is committed to translating research discoveries made in its laboratory. Several start-up companies and licenses have been generated from the laboratory, in particular, the start-up companies GenEdit, BioAmp Diagnostics and Microbial Medical were formed based upon research conducted in the Murthy lab.
This presentation will be given through zoom, please join us in 2405 Siebel Center for Computer Science, or join virtually on zoom at:
Pizza will be served following the presentation.