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The Development of Targeted Photosen...

Digby, Elyse Marie.

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The Development of Targeted Photosensitizers to Enhance the Efficacy and Selectivity of Photodynamic Therapy Against Cancer.

Record Type:	Electronic resources : Monograph/item
Title/Author:	The Development of Targeted Photosensitizers to Enhance the Efficacy and Selectivity of Photodynamic Therapy Against Cancer./
Author:	Digby, Elyse Marie.
Published:	Ann Arbor : ProQuest Dissertations & Theses, : 2023,
Description:	277 p.
Notes:	Source: Dissertations Abstracts International, Volume: 85-01, Section: B.
Contained By:	Dissertations Abstracts International85-01B.
Subject:	Chemistry. -
Online resource:	https://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=30417407
ISBN:	9798379771669

The Development of Targeted Photosensitizers to Enhance the Efficacy and Selectivity of Photodynamic Therapy Against Cancer.
Digby, Elyse Marie.

The Development of Targeted Photosensitizers to Enhance the Efficacy and Selectivity of Photodynamic Therapy Against Cancer. - Ann Arbor : ProQuest Dissertations & Theses, 2023 - 277 p.

Source: Dissertations Abstracts International, Volume: 85-01, Section: B.

Thesis (Ph.D.)--University of Toronto (Canada), 2023.

This item must not be sold to any third party vendors.

Photodynamic therapy is a clinically approved cancer therapeutic that uses a photosensitizer, light, and oxygen to produce reactive oxygen species. The accumulation of reactive oxygen species (e.g., singlet oxygen) can induce cancer cell death via oxidative damage, with the intracellular location of a photosensitizer a key determinant governing the outcome of photodynamic therapy. Although photodynamic therapy is inherently targeted due to light irradiation, currently used photosensitizers lack cancer cell selectively, making off-target accumulation and production of reactive oxygen species in the desired tissues problematic. Moreover, the low-energy visible light used to activate the photosensitizer has limited tissue penetration depth, such that the intracellular location of the photosensitizer becomes more crucial. In this thesis, I demonstrate approaches for overcoming these challenges with photodynamic therapy. I first discuss Br-DAPI, a DNA-binding photosensitizer that localizes to the nucleus and induces double-strand DNA breaks upon irradiation. I next describe a dual-targeted photosensitization strategy, where a conjugate containing two photosensitizers (Br-DAPI and Winter Green) localize to different subcellular organelles, where synergistic photocytotoxicity was achieved. Next, I seek to address the limitations with cancer selectivity and limited light penetration depth. To achieve cancer selectivity, I chemically modified a known photosensitizer, phenalenone, with a quinone substrate of human NAD(P)H:quinone oxidoreductase 1. When attached to the quinone, phenalenone is initially quenched in its ability to produce singlet oxygen, however phenalenone is liberated in the presence of cancer cells containing high levels of the enzyme (i.e., lung cancer cells), resulting in the production of cytotoxic singlet oxygen upon irradiation. To produce reactive oxygen species without the requirement of an external light source, I functionalized a chemiluminescent scaffold (i.e., Schaap's adamantylidene-dioxetane) with the photosensitizer, Erythosin B, where deprotonation of the reactive phenol (modifiable with an enzyme responsive trigger) resulted in spontaneous chemiluminescent resonance energy transfer to the photosensitizer and production of singlet oxygen in cancer cells. The four projects in this thesis propose proof-of-principle designs to address key limitations with photodynamic therapy. The key molecules discussed demonstrate evidence to improve the efficacy of photodynamic therapy and lay the groundwork for future optimization such that they can be applicable in vivo models.

ISBN: 9798379771669Subjects--Topical Terms:

516420
Chemistry.
Subjects--Index Terms:

Cancer

The Development of Targeted Photosensitizers to Enhance the Efficacy and Selectivity of Photodynamic Therapy Against Cancer.
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