Synthesis and Evaluation of Asymmetric Zinc and Phosphorous Pc Photosensitizers for Mitochondrial Targeted Photodynamic Therapy

Persistent Link:
http://hdl.handle.net/10150/581326
Title:
Synthesis and Evaluation of Asymmetric Zinc and Phosphorous Pc Photosensitizers for Mitochondrial Targeted Photodynamic Therapy
Author:
Muli, Dominic Kyalo
Issue Date:
2015
Publisher:
The University of Arizona.
Rights:
Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
Embargo:
Release 06-Aug-2016
Abstract:
Cancer remains a global pandemic and is rapidly overtaking other diseases as the no.1 killer in developing nations. Photodynamic therapy (PDT) has been advanced as a minimally invasive cancer therapy. In addition, the emergence of harmful microbes with increasing resistance to drugs has prompted the employment of photodynamic antimicrobial chemotherapy (PACT) as a promising alternative to combat antibiotic resistance. In PDT and PACT, a photosensitizer (dye/drug) upon activation by light transfers energy to molecular oxygen producing singlet oxygen which kills cells. There is increased attention and research into more selective and non-aggregated photosensitizers that will better PDT in treating cancer. This research work is focused on design and synthesis of non-aggregated asymmetric phthalocyanines (dyes) tagged with mitochondrial targeting vehicles to maximize selectivity and photo-killing of tumor cells. Chapter 1 presents a brief review of the current status of PDT and treatment of cancer. The three components of PDT namely, light, oxygen and the photosensitizer, are briefly discussed giving a concise overview of the development of each of them in bettering PDT as an alternative to cancer therapy. Chapter 2 outlines the design, synthesis and characterization of two non-aggregated symmetric ZnPc isomers that have improved water solubility due to incorporation of triethylene glycol groups. The extension of the max absorption to near-IR via non-peripheral substitution on the Pc macrocycle is reported, while comparing the photophysical characteristics of both isomers. Chapter 3 details the improved selectivity of photosensitizers by conjugating ZnPcs to rhodamine B, a delocalized lipophilic cation, which targets the mitochondria of the cell. This conjugation achieved 70% more cell death suggesting that incorporation of rhodamine improved cellular uptake and localization of the photosensitizers which is crucial. Chapters 4 and 5 cover the design, synthesis, characterization, and photodynamic therapy evaluation of ZnPc and phosphorous phthalocyanines. Introduction of phosphorous as an electron deficient central atom promoted a 42 nm bathochromic shift relative to the corresponding ZnPc isomer. Additionally, the effect of peripheral and non-peripheral substitution on phototoxicity of these new compounds is studied and reported. Chapter 5 also gives concluding remarks, and future directions of this work.
Type:
text; Electronic Dissertation
Keywords:
Near-IR absorption; Non-aggregation; Photodynamic Therapy; Water-soluble; Chemistry; Mitochondrial Targeting
Degree Name:
Ph.D.
Degree Level:
doctoral
Degree Program:
Graduate College; Chemistry
Degree Grantor:
University of Arizona
Advisor:
McGrath, Dominic

Full metadata record

DC FieldValue Language
dc.language.isoen_USen
dc.titleSynthesis and Evaluation of Asymmetric Zinc and Phosphorous Pc Photosensitizers for Mitochondrial Targeted Photodynamic Therapyen_US
dc.creatorMuli, Dominic Kyaloen
dc.contributor.authorMuli, Dominic Kyaloen
dc.date.issued2015en
dc.publisherThe University of Arizona.en
dc.rightsCopyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.en
dc.description.releaseRelease 06-Aug-2016en
dc.description.abstractCancer remains a global pandemic and is rapidly overtaking other diseases as the no.1 killer in developing nations. Photodynamic therapy (PDT) has been advanced as a minimally invasive cancer therapy. In addition, the emergence of harmful microbes with increasing resistance to drugs has prompted the employment of photodynamic antimicrobial chemotherapy (PACT) as a promising alternative to combat antibiotic resistance. In PDT and PACT, a photosensitizer (dye/drug) upon activation by light transfers energy to molecular oxygen producing singlet oxygen which kills cells. There is increased attention and research into more selective and non-aggregated photosensitizers that will better PDT in treating cancer. This research work is focused on design and synthesis of non-aggregated asymmetric phthalocyanines (dyes) tagged with mitochondrial targeting vehicles to maximize selectivity and photo-killing of tumor cells. Chapter 1 presents a brief review of the current status of PDT and treatment of cancer. The three components of PDT namely, light, oxygen and the photosensitizer, are briefly discussed giving a concise overview of the development of each of them in bettering PDT as an alternative to cancer therapy. Chapter 2 outlines the design, synthesis and characterization of two non-aggregated symmetric ZnPc isomers that have improved water solubility due to incorporation of triethylene glycol groups. The extension of the max absorption to near-IR via non-peripheral substitution on the Pc macrocycle is reported, while comparing the photophysical characteristics of both isomers. Chapter 3 details the improved selectivity of photosensitizers by conjugating ZnPcs to rhodamine B, a delocalized lipophilic cation, which targets the mitochondria of the cell. This conjugation achieved 70% more cell death suggesting that incorporation of rhodamine improved cellular uptake and localization of the photosensitizers which is crucial. Chapters 4 and 5 cover the design, synthesis, characterization, and photodynamic therapy evaluation of ZnPc and phosphorous phthalocyanines. Introduction of phosphorous as an electron deficient central atom promoted a 42 nm bathochromic shift relative to the corresponding ZnPc isomer. Additionally, the effect of peripheral and non-peripheral substitution on phototoxicity of these new compounds is studied and reported. Chapter 5 also gives concluding remarks, and future directions of this work.en
dc.typetexten
dc.typeElectronic Dissertationen
dc.subjectNear-IR absorptionen
dc.subjectNon-aggregationen
dc.subjectPhotodynamic Therapyen
dc.subjectWater-solubleen
dc.subjectChemistryen
dc.subjectMitochondrial Targetingen
thesis.degree.namePh.D.en
thesis.degree.leveldoctoralen
thesis.degree.disciplineGraduate Collegeen
thesis.degree.disciplineChemistryen
thesis.degree.grantorUniversity of Arizonaen
dc.contributor.advisorMcGrath, Dominicen
dc.contributor.committeememberMcGrath, Dominicen
dc.contributor.committeememberBandarian, Vaheen
dc.contributor.committeememberChristie, Hamishen
dc.contributor.committeememberMash, Eugeneen
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