|dc.description.abstract||Ordered supramolecular polymers are one-dimensional (1D) nanostructures formed by spontaneous association of molecular building units through non-covalent interactions. The construction of supramolecular polymers, often classified as a bottom-up approach, involves the self-organization of smaller building units into hierarchically complex structures. This approach has led to the development of synthetic materials that serve as extraordinary candidates for use in energy and medicine. To rationally design functional materials with desired properties, the critical feature ultimately lies in the design parameters of the constituents that determine the intermolecular interactions and affect the assembling behaviors or functions. In-depth understanding of such systems is therefore crucial to create self-assembled materials that overcome current and future challenges in their applications.
Peptide-based molecules offer an excellent synthetic platform to fabricate such supramolecular polymers through self-assembly in aqueous environments. Although self-assembly of amphiphilic peptides containing a β-sheet rich segment into 1D structures has been well-documented, little is known as to how the molecular architecture of the building blocks affects the self-organization into different types of 1D assemblies (such as nanofibers, nanoribbons, or nanotubes). For instance, branched chemical structures, though often considered as a flexible design for developing multifunctional block copolymers, are rarely introduced in peptidic systems. This thesis is aimed to develop peptide-based functional materials with potential applications in drug delivery or as cell scaffolding materials, by elucidating the structure-property relationship of the building blocks with the resulting macromolecular materials. Primarily focusing on the fabrication of 1D structures, we demonstrate the possibility of using molecular design to control three critical features of ordered supramolecular polymers as biomaterials: 1) the morphology of the assemblies, 2) the enzymatic degradability, and 3) the rheological properties.
We first investigated the requirements for designing nanotubes/nanofibers self-assembled by drug-peptide conjugates. Conjugation of an anticancer drug, camptothecin (CPT), into a peptidic segment enables the molecule to assemble into 1D structures given the strong directional interactions (hydrogen bonds or π-π stacking) among the building units. It was found that through the use of catanionic mixing or metal-coordination, the induced change of packing geometry of building units could determine whether these drug-peptide conjugates eventually assemble into nanotubes or nanofibers during 1D growth. In these cases, the change from a more conical-like to a less conical-like geometry could be tuned by the formation of ion-paired amphiphiles in catanionic mixing, or by coordination between designed hydroxamate groups and Fe(III) ions. This change in molecular packing could dictate the self-assembly from forming nanofibers into nanotubes. This discovery offers insight into rational design of proper peptidic molecules with predictable assembling morphologies.
Secondly, a platform of branched peptides was introduced, and we exploit this particular molecular design to fabricate filamentous networks for two purposes. The first example is the combined use of this molecular design and a crosslinking strategy to develop modeling materials for mimicking the extracellular matrix (ECM), incorporated with matrix metalloproteinase (MMP) specific degradability. This strategy was initiated through the design of an amphiphilic peptide that could undergo a rapid morphological transition in response to pH variations—where the assembled filaments existed in pH 4.5 but quickly dissociated in pH 7.5. And then MMP specific peptide substrates were introduced as crosslinkers to covalently fix the filaments in the self-assembled state. The crosslinked filaments were stable at pH 7.5, but gradually broke down into much shorter filaments upon cleavage of the peptidic crosslinkers by MMP. This platform is believed to be useful for the creation of supramolecular filaments responsive to enzymatic degradation. The next example continued the use of the branched construct for designing isomeric molecules to fine-tune the local viscoelastic properties of supramolecular polymers while maintaining similar surface chemistry and mesh size. The stiffness of 3D matrices, probed by particle-tracking microrheology, could be correlated with the degree of molecular packing order within the hydrophobic cores of the 1D assemblies.
The findings featured in this thesis provide in-depth understanding of the key role of the molecular design parameters in defining their functions, assembling behaviors, and potential applications in chemical, biomolecular and biomedical engineering.||