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

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

Bibliographic Details
Main Author: Wallace, Ashley J.
Language:English
Published: The Ohio State University / OhioLINK 2017
Subjects:
Chemistry
Biochemistry
Self-Assembly
Peptide Amphiphiles
Stimuli-Responsive
MRI
Water Relaxivity
Cancer Imaging
Cancer Targeting
Online Access:http://rave.ohiolink.edu/etdc/view?acc_num=osu1500485484867638
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spelling ndltd-OhioLink-oai-etd.ohiolink.edu-osu15004854848676382021-08-03T07:03:22Z pH-triggered Self-Assembly of a PEGylated Peptide Amphiphilic Contrast Agent Wallace, Ashley J. Chemistry Biochemistry Self-Assembly Peptide Amphiphiles Stimuli-Responsive MRI Water Relaxivity Cancer Imaging Cancer Targeting 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. 2017 English text The Ohio State University / OhioLINK http://rave.ohiolink.edu/etdc/view?acc_num=osu1500485484867638 http://rave.ohiolink.edu/etdc/view?acc_num=osu1500485484867638 unrestricted This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws.
collection NDLTD
language English
sources NDLTD
topic Chemistry
Biochemistry
Self-Assembly
Peptide Amphiphiles
Stimuli-Responsive
MRI
Water Relaxivity
Cancer Imaging
Cancer Targeting
spellingShingle Chemistry
Biochemistry
Self-Assembly
Peptide Amphiphiles
Stimuli-Responsive
MRI
Water Relaxivity
Cancer Imaging
Cancer Targeting
Wallace, Ashley J.
pH-triggered Self-Assembly of a PEGylated Peptide Amphiphilic Contrast Agent
author Wallace, Ashley J.
author_facet Wallace, Ashley J.
author_sort Wallace, Ashley J.
title pH-triggered Self-Assembly of a PEGylated Peptide Amphiphilic Contrast Agent
title_short pH-triggered Self-Assembly of a PEGylated Peptide Amphiphilic Contrast Agent
title_full pH-triggered Self-Assembly of a PEGylated Peptide Amphiphilic Contrast Agent
title_fullStr pH-triggered Self-Assembly of a PEGylated Peptide Amphiphilic Contrast Agent
title_full_unstemmed pH-triggered Self-Assembly of a PEGylated Peptide Amphiphilic Contrast Agent
title_sort ph-triggered self-assembly of a pegylated peptide amphiphilic contrast agent
publisher The Ohio State University / OhioLINK
publishDate 2017
url http://rave.ohiolink.edu/etdc/view?acc_num=osu1500485484867638
work_keys_str_mv AT wallaceashleyj phtriggeredselfassemblyofapegylatedpeptideamphiphiliccontrastagent
_version_ 1719452794431209472

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