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pH-triggered Self-Assembly of a PEGylated Peptide Amphiphilic Contrast Agent

Wallace, Ashley J.
http://orcid.org/0000-0002-5415-8271
http://rave.ohiolink.edu/etdc/view?acc_num=osu1500485484867638

Abstract Details

2017, Doctor of Philosophy, Ohio State University, Chemistry.
Self-assembling peptide amphiphiles (PAs) have gained significant interest in the area of “smart” nano-diagnostics and therapeutics due to their ability to form different morphologies in response to various physiological stimuli. For cancer targeting, it is ideal that these PAs respond to a broad hallmark associated with tumors and not specific biomarkers that evolve constantly. Developing PA based dynamic imaging agents that transform into a larger, more slowly-diffusing morphology in response to a generic cancer hallmark can allow for the selective accumulation of such agents in high concentrations at the tumor site to enhance the sensitivity and resolution of traditional imaging techniques. One particularly attractive cancer hallmark is the acidic extracellular microenvironment (pHe = 6.6-7.4) that results from the high rate of glycolytic metabolism in tumor tissues, as well as the enhanced permeation and retention (EPR) of nano-sized diagnostic and therapeutic agents (ideally 10-30 nm) arising from their leaky vasculature system. We have previously developed PAs that respond to the differences in the pHe and physiological pH via undergoing a morphological transition from spherical micelles (10-15 nm) to nanofibers (> 1 µm in length, 10-15 nm) in isotonic salt solutions simulating the ionic strength of blood serum. Using the solid phase technique, each PA was synthesized to incorporate 4 specific regions: a hydrophobic (alkyl) tail, a ß-sheet region, a region of charged amino acids, and a Magnetic Resonance Imaging (MRI) moiety that consists of a Gd-chelator, to enable this transition in the desired pH range. The small diameter of the micelles is expected to maximize tumor penetration, and the much larger, much more slowly diffusing nanofibers formed in the tumor’s interstitial microenvironment will maximize retention, thereby allowing cancer detection with high signal and sensitivity. PEGylation, or addition of polyethylene glycol units, to diagnostic and therapeutic vehicles has been extensively used to increase their blood circulation half-life. Covalent linkage of these units work by 1) providing a protective coat that reduces recognition, degradation, and elimination from the bloodstream by the body’s immune system and 2) increasing the apparent size of the molecule as to reduce renal clearance. Previous Research have shown that the addition of these units modifies physical features of a molecule but do not affect their functions. Here, we investigate the effects of various PEGylation ratios on the pH-triggered self-assembly. Circular dichroism, critical aggregation concentration and transmission electron microscopy measurements will be used to characterize morphology transitions at various concentrations and pH values of the PA. Fluorescence anisotropy using a fluorophore-labeled PA will be used to probe self-assembly behavior in blood serum. Finally, the rate of water relaxation will be investigated to understand the efficiency of these agents to be used for MRI.
Joshua Goldberger (Advisor)
David Nagib (Committee Member)
David Tomasko (Committee Member)
Claudia Turro (Committee Member)
160 p.
Biochemistry; Chemistry
Self-Assembly; Peptide Amphiphiles; Stimuli-Responsive; MRI; Water Relaxivity; Cancer Imaging; Cancer Targeting

Recommended Citations

Citations

  • Wallace, A. J. (2017). pH-triggered Self-Assembly of a PEGylated Peptide Amphiphilic Contrast Agent [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1500485484867638

    APA Style (7th edition)

  • Wallace, Ashley. pH-triggered Self-Assembly of a PEGylated Peptide Amphiphilic Contrast Agent. 2017. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1500485484867638.

    MLA Style (8th edition)

  • Wallace, Ashley. "pH-triggered Self-Assembly of a PEGylated Peptide Amphiphilic Contrast Agent." Doctoral dissertation, Ohio State University, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=osu1500485484867638

    Chicago Manual of Style (17th edition)

osu1500485484867638
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This open access ETD is published by The Ohio State University and OhioLINK.
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