Peptide Amphiphile micelles (pams)-biomolecular materials capeble of modulating the immune system
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[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI SYSTEM AT AUTHOR'S REQUEST.] Peptide based therapeutics have become increasingly popular due to their ease of design and production. The low molecular weight and limited physiological stability often prevents peptides from reaching their desired target and carrying out their desired performance. This dissertation focuses on utilizing peptide amphiphile micelles (PAMs), a type of professional delivery vehicle that has been used to enhance peptide therapeutic efficacy for a variety of different applications. My work has specifically uncovered that through modulating micelle physical properties (i.e. size and charge) and incorporating carefully selected peptide sequences, PAMs can be designed that either enhance or alter immune responses, which I have leveraged to achieve novel immunization and anti-inflammatory responses. In the opening chapter, I review important rules for designing synthetic vaccines as well as common techniques used to assess vaccine physical properties and biological efficacy. This chapter is retrieved from my publication in the Journal of Bionanoscience. In the second chapter, I introduce ways to create higher order micellar structures through the inclusion of a zwitterion-like region (i.e. oligolysylglutamate). This work represents the first use of electrostatic interactions to drive further micelle association beyond hydrophobically driven self-assembly. Additionally, PAM size and shape can be modulated by altering peptide amphiphile chemistry. This is crucial for PAM vaccine development as size has been previously reported to have tremendous impact on immunogenicity. This chapter is adapted from my publication in ACS Biomaterials Science & Engineering. In the third chapter, I assessed the immunogenicity of the higher-order micellar structures formulated in Chapter 2 as well as PAMs with different surface charge. These efforts led to the discovery that PAM physical properties are closely related to their immunogenicity. Specifically, we developed PAM structures that are either immunopotentiating (i.e. improve antigen immunogenicity) or immunoisolating (i.e. diminish antigen immunogenicity). These exciting results directed my further research in two distinct directions: immune activation (Chapters 4 and 5) and immune suppression (Chapter 6). The third chapter is adapted from my publication in ACS Biomaterials Science & Engineering. In the next two chapters, I incorporated two different adjuvants (i.e. Pam[subscript]2C -- Chapter 4, CpG -- Chapter 5) into the most immunogenic structures (i.e. moderately positively charged spherical and shorty cylindrical PAMs). In order to achieve antigen|adjuvant co-localization, several different chemical and engineering methods were utilized. Results indicated that the method used to achieve antigen|adjuvant co-localization dramatically impacts bioactivity. Chapter 4 is adapted is adapted from my publication in The AAPS Journal and Chapter 5 is adapted from a manuscript to be submitted to Molecular Pharmaceutics. In the final research chapter, we investigated an immunosuppressive peptide, vasoactive intestinal peptide (VIP), instead of an immunogenic epitope. By incorporating this different bioactive peptide into different PAM structures, I was able to design anti-inflammatory micelles capable of achieving size-dependent immunosuppressive effects. This chapter is adapted from my publication in Biomaterials Science. In the final chapter, I discuss the future opportunities possible by leveraging the fundamental immunomodulatory PAM results I have generated to date.
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