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Biochemistry & Molecular Biology
Lipid micelles represent an important class of nanoparticle with the potential to enhance the solubility and delivery of hydrophobic drugs and imaging agents. Their small size (< 50 nm) makes them ideal candidates for both passive tumor uptake and deep tissue penetration. The use of lipid micelles as delivery vehicles, however, has been challenged by the fact that these particles are inherently unstable in vivo due to concentration dependence and interactions with serum proteins. We have developed a minimalist method, which we are working to optimize, in order to stabilize the formation of micelles using lipid monomers covalently modified with short oligonucleotide sequences (16 nucleotides in length). Micellar structure can be easily tuned in this approach by modifying lipid structure and oligonucleotide sequence, thus creating a library of micelles with varying stability. These oligonucleotide-lipid conjugates are synthesized manually using standard phosphoramidite chemistry. Lipid phosphoramidite synthesis was confirmed using 31P NMR, and synthesis of lipid-oligonucleotide conjugates was confirmed by gel electrophoresis and HPLC. Our results show that we have successfully synthesized, and purified DNA-lipid conjugates composed of 16 carbon (C16) or 18 carbon (C18) tails with 1 (monoacyl) or two (diacyl) chains. Future studies will involve further stability and size measurements. This approach provides a pathway toward the engineering of programmable micelles such that an external trigger leads to monomer exchange with serum proteins and cargo release.
Yanoff, Zenya and Wun, Jesse, "Synthesis and Assembly of Oligonucleotide-Stabilized Lipid Micelles" (2021). Biochemistry and Molecular Biology Summer Fellows. 19.
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