3-Helix Micelles as Nanocarriers – Understanding Hierarchical Structures, Kinetic Pathway, and Controlling Multivalency

摘要: This dissertation focuses on fundamental understanding of the hierarchical nanostructure and kinetic pathway self-assembled sub-20 nm 3-helix micelles. micelles are formed by self-assembly a new family amphiphilic peptide-PEG-lipid hybrid conjugates. Structural deconvolution this complex, hierarchically assembled multi-component system is non-trivial delineating structural components crucial to reveal insights into organization building block constituents. Furthermore, decoupling effect each component imperative appreciate their contribution towards overall energy landscape for future design nanocarriers. The knowledge gained from these studies provides insight identify parameters that will facilitate development nanocarriers based micelles.3-helix demonstrate immense potential as nanocarrier drug delivery brain due its ability bypass blood-brain barrier accumulate within glioblastoma tumors in rat models. To bridge gap between biological performance structure-function correlation, structure assembly studied detail.Unraveling internal micelle using contrast variation small-angle neutron scattering revealed slightly deformed side-conjugated PEG ~85 v/v% comprised water. entropic deformation likely contributes high stability whereas water content has significant repercussions mechanical properties could shed light extravasation through barriers.The conjugates at air-water interface form trimeric coiled-coils was shown be dependent applied lateral pressure. PEGylated amphiphiles bundle-forming peptides mixture dimers trimers intermediate pressure converts completely upon surface acts mediate interaction bundles preserves coiled-coil integrity compression.The formation also delineated understand role toward process. key factor determining corona micelles, providing greater energetic barriers subunits overcome dissociate micelle. Hydrophobic packing alkyl chains lesser degree stability, but plays reorganization during coiled-coils.The aspects process two coiled-coil-based generate mixed platform control over local multivalent state ligands surface. Tracking distribution indicated they phase separate regions enriched one amphiphile. ligand presentation well generation ‘patchy’ suggests ligand-targeted applications.Lastly, conjugation architecture di-alkyl attached peptide headgroup probe how can influence stability. results showed highly splayed pack more efficiently, leading enhanced melting transition temperatures increased without significantly disrupting secondary tertiary structure. demonstrates useful parameter manipulate