Electron-deficient Alkyne Lipids Enable Efficient Synthesis of Polymer Lipids via Cu-free Azide-Alkyne Cycloaddition
Florian T. Kaps1, Anna-Lena Ziegler1, Paul Fritsche1, Ekaterina Takmakova1, Andrew Kerr1, Susanne Boye2, Albena Lederer2,3 and Robert Luxenhofer1,*
1 Soft Matter Chemistry, Department of Chemistry, and Helsinki Institute of Sustainability Science, Faculty of Science, University of Helsinki, Helsinki 00014, Finland
2Leibniz-Institut für Polymerforschung, Center Macromolecular Structure Analysis, Hohe Str. 6, 01069 Dresden, Germany
3Stellenbosch University, Department of Chemistry and Polymer Science, Private Bag X1, Matieland 7602, South Africa
Polymer lipids (PLs) are essential components of liposomes and lipid nanoparticles (LNPs) for drug and gene delivery, providing colloidal stabilization and defining the biological interface. While poly(ethylene glycol) (PEG)-based PLs are the current standard, they are suspected to be responsible for rare adverse reactions, e. g. to LNP-based Covid-19 vaccines.[1] Therefore, PLs based on alternative stealth polymers, such as Poly(2-ethyl-2-oxazoline)[2] or Poly(sarcosine)[3], are being intensively investigated for their use in LNPs. However, these alternative PLs often lack comparability due to different synthesis protocols and are not easily accessible. In this work, we present a catalyst-free, efficient and versatile coupling procedure for PL synthesis based on azide-functionalized polymers and electron-deficient acetylene dicarboxylate lipids (ADC Lipids). This approach allows to obtain comparable PLs comprising an identical triazole linker. To highlight the versatility, we prepared PLs based on PEG and 4 alternative stealth polymers with quantitative coupling efficiencies. The introduced linker structure showed appropriate cytocompatibility, biocompatibility and pH stability. In addition, all PLs enabled the preparation of well-defined liposomes with excellent stability. Taken together, our facile and versatile approach yields comparable PLs with minimized linker size, that are promising candidates for future comparative studies and biomedical applications.
[1] Bigini, P.; Gobbi, M.; Bonati, M.; Clavenna, A.; Zucchetti, M.; Garattini, S.; Pasut, G. The role and impact of polyethylene glycol on anaphylactic reactions to COVID-19 nano-vaccines. Nature Nanotechnology 2021, 16 (11), 1169-1171.
[2] Sanchez, A. J. D. S.; Loughrey, D.; Echeverri, E. S.; Huayamares, S. G.; Radmand, A.; Paunovska, K.; Hatit, M.; Tiegreen, K. E.; Santangelo, P. J.; Dahlman, J. E. Substituting Poly(ethylene glycol) Lipids with Poly(2-ethyl-2-oxazoline) Lipids Improves Lipid Nanoparticle Repeat Dosing. Advanced Healthcare Materials 2024, 13 (17), 2192-2640.
[3] Kang, D. D.; Hou, X.; Wang, L.; Xue, Y.; Li, H.; Zhong, Y.; Wang, S.; Deng, B.; McComb, D. W.; Dong, Y. Engineering LNPs with polysarcosine lipids for mRNA delivery. Bioactive Materials 2024, 37, 86-93.