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Permanent link (DOI): https://doi.org/10.7939/R35T3GD2Z

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Exploiting the Enhanced Permeability and Retention Effect for the Targeting of Tumors with 18F-SiFA Polymer Nanoparticles Open Access

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Other title
Subject/Keyword
EPR effect
angiogenesis
oncology
radiolabeling
SiFA
nanoparticle
fluorine-18
PET
Type of item
Thesis
Degree grantor
University of Alberta
Author or creator
Berke, Sheldon S
Supervisor and department
Dr. Ralf Schirrmacher (Oncology)
Examining committee member and department
Dr. John Lewis (Oncology)
Dr. Ralf Schirrmacher (Oncology)
Dr. Jonathan Veinot (Chemistry)
Dr. Frank Wuest (Oncology),
Department
Department of Oncology
Specialization
Cancer Sciences
Date accepted
2017-09-28T10:14:28Z
Graduation date
2017-11:Fall 2017
Degree
Master of Science
Degree level
Master's
Abstract
Over the last several decades great progress has been made in cancer diagnosis and detection. One foundation of this progress has been improved imaging technologies. Among the most promising imaging technologies for cancer detection is Positron Emission Tomography (PET). PET imaging allows for visualization of cancerous tissue through the utilization of positron emitting radioactive nuclides attached to biomolecules, which are designed to target the unique characteristics of cancerous cells. Current radiotracers, mostly small molecules, monoclonal antibodies, and peptides have shown varying degrees of clinical success. In most cases serious limitations exist which prevent their use in more than a fraction of cancers1. Recently, a unique cancer characteristic has shown vulnerability to targeting, a trait existing in almost all solid tumors. Solid tumors have a unique vascular architecture in comparison with normal tissue. Vascular defects and poor lymphatic drainage result in solid tumors possessing a unique physiological environment. These abnormal conditions facilitate the accumulation of nanometer-sized particles. Exploiting this phenomenon, known as the enhanced permeability and retention (EPR) effect, with functionalized nanoparticles may lead to new diagnostics and therapies of cancer. To further understand the EPR effect, a range of polymer nanoparticles (PNPs) of distinct sizes, from 10 nm to 130 nm , were synthesized and functionalized with the Silicon-Fluoride Acceptor (SiFA) isotopic exchange technology (PNP1-PNP3, PNP5-PNP14). This SiFA group allows for simple and rapid fluorine-18 labeling under mild conditions. PNPs were chosen due to their ease of functionalization, low inherent toxicity, and extensive tunability. Optimal radiolabeling methodologies were established, including green chemistry conditions, resulting in fluorine-18 incorporation from 59 - 79% and radiochemical yields ranging from 28 – 43%. Purification of PNPs was iii achieved through size exclusion chromatography. Four 18F-labeled PNPs (sizes: 20 nm, 33 nm, 45 nm, and 72 nm) were then chosen for injection into EMT-6 tumor bearing mice and their biodistribution was observed over a time course of 4-hours p.i. PET scan. Biodistribution studies determined that both organ and tumor uptake were dependent on PNP size. Furthermore, tumor accumulation for several 18F-PNPs (33 nm, 45 nm, and 72 nm) increased from 1- to 4-hours p.i.. This work revealed that the 33 nm nanoparticle, 18F-PNP5, was the most effective 18F-PNP for tumor targeting, displaying a tumor SUVmean of 0.97 and a tumor to muscle ratio of 4.22 at 4-hours p.i.. These results compare favorably with other classes of tumor targeting PET agents and reveal that SiFA-radiolabeled PNPs, specifically in the 30 nm range, should be further evaluated as tumor-targeting agents in this specific tumor model.
Language
English
DOI
doi:10.7939/R35T3GD2Z
Rights
This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for the purpose of private, scholarly or scientific research. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.
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