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Formulation and Characterization of Protein and Peptide Nanoparticles for Targeting the Acidic Tumor Microenvironment
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Formulation and Characterization of Protein and Peptide Nanoparticles for Targeting the Acidic Tumor Microenvironment
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Formulation and Characterization of Protein and Peptide Nanoparticles for Targeting the Acidic Tumor Microenvironment
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Dissertation
Formulation and Characterization of Protein and Peptide Nanoparticles for Targeting the Acidic Tumor Microenvironment
2017
Overview
This dissertation outlines work completed on formulating and characterizing protein and peptide nanoparticles, with the ultimate goal of targeting these nanoparticles for pH-dependent drug delivery in the acidic tumor microenvironment. This study begins in Chapter Two with a basic exploration of the complexities and limitations of polyelectrolyte complex formation between poly(Glutamic-Acid) and poly(Lysine), as anion and cation, respectively. These complexes are shown to be highly controllable in size and dispersity, and a critical size limitation of 20 amino-acids is reported for successful PEC formation. This concept is then carried into Chapter Three, where the pH-responsive copolymer HEn is paired with poly(Lysine) to form a peptide nanoparticle capable of encapsulating the drug daunomycin, and degrading specifically in response to a decrease in pH to between 6.0-6.5. The next chapters take a slightly different approach, and focus on obtaining a change in nanoparticle surface charge in response to a decreased pH. Chapter Four discusses a novel formulation method for heat-stabilized albumin-only nanoparticles, which removes any need for use of toxic cross-linkers, and provides numerous opportunities for surface modification chemistries. These heat-stabilized nanoparticles are then surface-modified in Chapter Five with various analogues of imidazole, all of which have a pKa of approximately 6.5, allowing them to serve as biologic pH-switches. These surface modifications all result in similar in vitro cell association. To further analyze the potential for imidazole as a physiologically relevant pH-switch, Chapter Six looks at a direct comparison between heat-stabilized nanoparticles that were unmodified, particles modified with the single-imidazole DAH moiety, and particles modified with the di-imidazole DIPA moiety. The DIPA-modified nanoparticles both quantitatively and qualitatively demonstrate increased pH-sensitivity at pH 6.5 compared to 7.4, and increase in vitro cell association compared to the DAH or unmodified nanoparticles, making the DIPA-modified nanoparticles of particular interest for further study in targeting the acidic tumor microenvironment.
