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Controlling the Stability of Colloid...

Ganesh, Ahil Naban.

Controlling the Stability of Colloidal Drug Aggregates for Chemotherapeutic Delivery.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Controlling the Stability of Colloidal Drug Aggregates for Chemotherapeutic Delivery.
Author:	Ganesh, Ahil Naban.
Published:	Ann Arbor : ProQuest Dissertations & Theses, 2019
Description:	136 p.
Notes:	Source: Dissertations Abstracts International, Volume: 81-04, Section: B.
Notes:	Advisor: Shoichet, Molly S.
Contained By:	Dissertations Abstracts International81-04B.
Subject:	Chemical engineering.
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=13806311
ISBN:	9781085787727

Controlling the Stability of Colloidal Drug Aggregates for Chemotherapeutic Delivery.
Ganesh, Ahil Naban.

Controlling the Stability of Colloidal Drug Aggregates for Chemotherapeutic Delivery. - Ann Arbor : ProQuest Dissertations & Theses, 2019 - 136 p.

Source: Dissertations Abstracts International, Volume: 81-04, Section: B.

Thesis (Ph.D.)--University of Toronto (Canada), 2019.

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

Colloidal aggregation presents a significant nuisance in drug discovery programs; the self-assembly of hydrophobic compounds into colloidal particles leads to numerous artifactual results in screening assays. In biochemical enzyme inhibition assays colloids non-specifically adsorb proteins leading to partial unfolding and enzyme inactivation. In cell-based cytotoxicity assays colloids are unable to cross cell membranes leading to the drug being unable to bind to its intracellular target, resulting in apparent inactivity. Colloidal aggregation is not only common among drug screening candidates but also among clinically used drugs. Being composed entirely of active drug, colloidal drug aggregates have many properties that make them suitable as nanoparticle drug formulations. In this work, two methods to stabilize colloidal drug aggregates were developed to enable targeted delivery and in vivo utility. First, exploiting the ability of drug colloids to adsorb proteins, we formed controlled protein coronas to stabilize colloids in both buffered solutions and serum-containing media. Coronas comprising antibodies not only stabilized colloids but also enabled their specific internalization by target cells. Second, incorporation of amphiphilic surfactants during colloid formation resulted in a hydrophilic polymer layer that sterically stabilized drug colloids. Incorporation of surfactants significantly reduced protein adsorption, stabilizing drug colloids in serum-containing media. We designed methods to test colloid stability in high serum media in vitro based on co-aggregation with fluorescent FRET pairs. Finally, we investigated the influence of stable colloidal drug aggregates on the in vivo pharmacokinetics of chemotherapeutics. Stable colloidal formulations showed increased plasma circulation half-lives compared to solubilized, monomeric formulations. Overall, we demonstrate methods to stabilize, study and utilize colloidal drug aggregates, turning a nuisance into an opportunity for drug formulation.

ISBN: 9781085787727Subjects--Topical Terms:

206267
Chemical engineering.

Controlling the Stability of Colloidal Drug Aggregates for Chemotherapeutic Delivery.
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520 $a Colloidal aggregation presents a significant nuisance in drug discovery programs; the self-assembly of hydrophobic compounds into colloidal particles leads to numerous artifactual results in screening assays. In biochemical enzyme inhibition assays colloids non-specifically adsorb proteins leading to partial unfolding and enzyme inactivation. In cell-based cytotoxicity assays colloids are unable to cross cell membranes leading to the drug being unable to bind to its intracellular target, resulting in apparent inactivity. Colloidal aggregation is not only common among drug screening candidates but also among clinically used drugs. Being composed entirely of active drug, colloidal drug aggregates have many properties that make them suitable as nanoparticle drug formulations. In this work, two methods to stabilize colloidal drug aggregates were developed to enable targeted delivery and in vivo utility. First, exploiting the ability of drug colloids to adsorb proteins, we formed controlled protein coronas to stabilize colloids in both buffered solutions and serum-containing media. Coronas comprising antibodies not only stabilized colloids but also enabled their specific internalization by target cells. Second, incorporation of amphiphilic surfactants during colloid formation resulted in a hydrophilic polymer layer that sterically stabilized drug colloids. Incorporation of surfactants significantly reduced protein adsorption, stabilizing drug colloids in serum-containing media. We designed methods to test colloid stability in high serum media in vitro based on co-aggregation with fluorescent FRET pairs. Finally, we investigated the influence of stable colloidal drug aggregates on the in vivo pharmacokinetics of chemotherapeutics. Stable colloidal formulations showed increased plasma circulation half-lives compared to solubilized, monomeric formulations. Overall, we demonstrate methods to stabilize, study and utilize colloidal drug aggregates, turning a nuisance into an opportunity for drug formulation.
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