Author

Weike Chen

ORCID Identifier(s)

0000-0003-2616-8525

Graduation Semester and Year

2022

Language

English

Document Type

Dissertation

Degree Name

Doctor of Philosophy in Chemistry

Department

Chemistry and Biochemistry

First Advisor

He Dong

Abstract

Supramolecular peptide-based biomaterials have attracted much attention from researchers in various science and engineering fields because of the ease of synthesis and precise control over structures and physicochemical properties on multiple length levels. Self-assembled peptides have shown great potential as functional biomaterials for both diagnosis and treatment of various diseases. In Chapter 1, I will introduce several self-assembled peptide systems in terms of molecular design, structure characterization, and their biological applications. In particular, I will discuss new peptide self-assemblies with trigger-responsive properties for targeted molecular imaging and therapy. In Chapter 2, I will focus on peptide self-assembly that can target the reductive tumor microenvironment for selective imaging of tumor cells. The in vitro fluorescence cell imaging demonstrated that assembling peptide precursors can undergo chemical and physical transformation to peptide nanofibers with multivalent display of tumor targeting ligands at the reductive tumor sites. These nanofibers show selective binding to U87mg tumor cells that have overexpression of integrin receptors, showing their potentials as tumor targeting probes. In Chapter 3, I will discuss the design and application of self-assembled peptides toward safe and effective antimicrobial therapy development. Natural antimicrobial peptides (AMPs) are potent to kill pathogenic bacteria, however it suffers from severe cytotoxicity against mammalian cells. To overcome the intrinsic limitation of natural AMPs, we incorporated them in a self-assembled antimicrobial nanofiber (SAANs) that our group developed previously. The integration of natural AMPs on SAANs greatly reduced the cytotoxicity against healthy cells but retained potent antimicrobial activity. The mechanism was elucidated through a combined biophysical and biochemical assay using lipid vesicles as a model membrane system. In Chapter 4, I further advanced our design to develop novel self-assembled peptide nanofibers with bacterial targeting capability. A series of responsive peptide nanofibers were generated that showed acid-triggered antimicrobial activity. The in vitro antimicrobial and hemocompatibility assay suggested that these nanofibers were nearly nontoxic toward human blood cells at neural physiological conditions but can selectively kill both Gram-positive and Gram-negative bacteria at acidic conditions. In Chapter 5, I will discuss the most recent results on the design of peptide self-assembly with alkaline-responsive antimicrobial activity. Given the urgent need to combat bacterial infections in diseases with an elevated pH, we synthesized a new type of alkaline-responsive antimicrobial hydrogel based on polydiacetylene-peptide (PDA-Pep). Upon pH elevation, the peptide domain is deprotonated and triggers the conformational change of the PDA domain, leading to a colorimetric transition from blue to purple. Simultaneously, the deprotonation induces a gel-to-sol macroscopic phase transition of the fiber network formed in PDA-Pep hydrogels, which causes a selective release of the antimicrobial agents that are encapsulated in the gels into the infection site to kill bacteria. The translational potential of PDA-Pep hydrogels for pH-sensing and on-demand alkaline-triggered antibiotic delivery were demonstrated on inoculated pig skins. The work lays the foundation for the development of multifunctional alkaline-responsive materials in which multiple small molecule or macromolecular therapeutics can be encapsulated to achieve synergistic biological functions against a wide range of multidrug-resistant pathogens.

Keywords

Supramolecular materials, Self-assembled peptide biomaterials, Tumor imaging, Antimicrobial therapy

Disciplines

Chemistry | Physical Sciences and Mathematics

Comments

Degree granted by The University of Texas at Arlington

Included in

Chemistry Commons

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