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Quinidine-Containing Polymers for Re...

Snyder, Sarah Marie.

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Quinidine-Containing Polymers for Reversal of P-Glycoprotein Mediated Drug Efflux in Multidrug Resistant Cancers.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Quinidine-Containing Polymers for Reversal of P-Glycoprotein Mediated Drug Efflux in Multidrug Resistant Cancers./
Author:	Snyder, Sarah Marie.
Published:	Ann Arbor : ProQuest Dissertations & Theses, : 2020,
Description:	181 p.
Notes:	Source: Dissertations Abstracts International, Volume: 82-04, Section: B.
Contained By:	Dissertations Abstracts International82-04B.
Subject:	Biomedical engineering. -
Online resource:	https://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=28086256
ISBN:	9798672146348

Quinidine-Containing Polymers for Reversal of P-Glycoprotein Mediated Drug Efflux in Multidrug Resistant Cancers.
Snyder, Sarah Marie.

Quinidine-Containing Polymers for Reversal of P-Glycoprotein Mediated Drug Efflux in Multidrug Resistant Cancers. - Ann Arbor : ProQuest Dissertations & Theses, 2020 - 181 p.

Source: Dissertations Abstracts International, Volume: 82-04, Section: B.

Thesis (Ph.D.)--Cornell University, 2020.

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

P-glycoprotein (P-gp) is a membrane protein innately expressed at barrier sites in the body, including the blood-brain barrier, intestines, and many different cancers. P-gp binds small molecules, termed "substrates," that present intracellularly and effluxes them to the cell exterior. These compounds include low molecular weight drugs, toxins, and metabolites, and their removal from tissues is typically protective. In cancer, P-gp recognizes a vast array of chemotherapeutic compounds as substrates, and its efflux activity results in prompt removal of these chemotherapeutics from cancer cells. This phenomenon imparts a cellular phenotype known as "multidrug resistance," or MDR, and prevents effective therapeutic drug concentrations from being maintained within the cancer cells. This dissertation explores the chemical conjugation of quinidine, a P-gp inhibitor, to polymers as a way to permit P-gp inhibition while mitigating off-target cardiac effects associated with intravenous quinidine. First, quinidine is bound at its hydroxyl group to a single poly(ethylene glycol) chain, the resulting conjugate's mechanism of action is verified, and its mitigated distribution into the myocardium is quantified. Next, a multivalent array of acrylic acid-quinidine copolymers are synthesized, chemically evaluated, and prepared for analysis of their biodistribution to P-gp bearing tissues in a rodent tumor xenograft model. This thesis highlights the capability of using the additions of polymers to quinidine to control its mechanism of action, mitigate its side effects, and tentatively influence biodistribution.

ISBN: 9798672146348Subjects--Topical Terms:

535387
Biomedical engineering.
Subjects--Index Terms:

Cancer

Quinidine-Containing Polymers for Reversal of P-Glycoprotein Mediated Drug Efflux in Multidrug Resistant Cancers.
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520 $a P-glycoprotein (P-gp) is a membrane protein innately expressed at barrier sites in the body, including the blood-brain barrier, intestines, and many different cancers. P-gp binds small molecules, termed "substrates," that present intracellularly and effluxes them to the cell exterior. These compounds include low molecular weight drugs, toxins, and metabolites, and their removal from tissues is typically protective. In cancer, P-gp recognizes a vast array of chemotherapeutic compounds as substrates, and its efflux activity results in prompt removal of these chemotherapeutics from cancer cells. This phenomenon imparts a cellular phenotype known as "multidrug resistance," or MDR, and prevents effective therapeutic drug concentrations from being maintained within the cancer cells. This dissertation explores the chemical conjugation of quinidine, a P-gp inhibitor, to polymers as a way to permit P-gp inhibition while mitigating off-target cardiac effects associated with intravenous quinidine. First, quinidine is bound at its hydroxyl group to a single poly(ethylene glycol) chain, the resulting conjugate's mechanism of action is verified, and its mitigated distribution into the myocardium is quantified. Next, a multivalent array of acrylic acid-quinidine copolymers are synthesized, chemically evaluated, and prepared for analysis of their biodistribution to P-gp bearing tissues in a rodent tumor xenograft model. This thesis highlights the capability of using the additions of polymers to quinidine to control its mechanism of action, mitigate its side effects, and tentatively influence biodistribution.
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