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Strategies for Prodrug Light Activat...

Holbrook, Robert J.

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Strategies for Prodrug Light Activation and Diagnostic Nanoparticle Conjugates through Coordination Chemistry.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Strategies for Prodrug Light Activation and Diagnostic Nanoparticle Conjugates through Coordination Chemistry./
Author:	Holbrook, Robert J.
Description:	244 p.
Notes:	Source: Dissertation Abstracts International, Volume: 76-10(E), Section: B.
Contained By:	Dissertation Abstracts International76-10B(E).
Subject:	Inorganic chemistry. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3705271
ISBN:	9781321781649

Strategies for Prodrug Light Activation and Diagnostic Nanoparticle Conjugates through Coordination Chemistry.
Holbrook, Robert J.

Strategies for Prodrug Light Activation and Diagnostic Nanoparticle Conjugates through Coordination Chemistry. - 244 p.

Source: Dissertation Abstracts International, Volume: 76-10(E), Section: B.

Thesis (Ph.D.)--Northwestern University, 2015.

Co(III) Schiff base (sb) complex derivatives of bis(acetylacetone) ethylenediimine [acacen] are potent protein inhibitors via exchange of labile axial ligands. Upon dissociation, Co(III) irreversibly interacts with essential histidine residues of the protein and disrupts function. In order to guide the rational design of prodrug agents, understanding the mechanism and dynamics of the ligand exchange process is essential. To investigate the lability, pH stability, and axial ligand exchange of these complexes in the absence of proteins, the axial ligand substitution dynamics of a series of N-heterocyclic Co(III)-sb complexes were prepared and characterized by NMR spectroscopy. These studies revealed [Co(acacen)(imidazole)2 ]+ as an ideal candidate for prodrug activation.

ISBN: 9781321781649Subjects--Topical Terms:

3173556
Inorganic chemistry.

Strategies for Prodrug Light Activation and Diagnostic Nanoparticle Conjugates through Coordination Chemistry.
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100 1 $a Holbrook, Robert J. $3 3192982
245 1 0 $a Strategies for Prodrug Light Activation and Diagnostic Nanoparticle Conjugates through Coordination Chemistry.
300 $a 244 p.
500 $a Source: Dissertation Abstracts International, Volume: 76-10(E), Section: B.
500 $a Adviser: Thomas J. Meade.
502 $a Thesis (Ph.D.)--Northwestern University, 2015.
520 $a Co(III) Schiff base (sb) complex derivatives of bis(acetylacetone) ethylenediimine [acacen] are potent protein inhibitors via exchange of labile axial ligands. Upon dissociation, Co(III) irreversibly interacts with essential histidine residues of the protein and disrupts function. In order to guide the rational design of prodrug agents, understanding the mechanism and dynamics of the ligand exchange process is essential. To investigate the lability, pH stability, and axial ligand exchange of these complexes in the absence of proteins, the axial ligand substitution dynamics of a series of N-heterocyclic Co(III)-sb complexes were prepared and characterized by NMR spectroscopy. These studies revealed [Co(acacen)(imidazole)2 ]+ as an ideal candidate for prodrug activation.
520 $a The activation of this biologically inert Co(III)-sb complex, to its protein inhibitor form, is achieved by photoinduced electron transfer (PET) from a colloidal PbS quantum dot (QD, radius = 1.5 nm) to Co(III) with a charge separation time constant of 114 ns. Reduction of the Co(III)-sb initiates release of the native axial ligands, imidazole, promoting replacement with the histidine mimic 4-methylimidazole. The rate of ligand displacement increases by a factor of eight upon exposure of the PbS QD/Co(III)-SB mixture upon irradiation with near-infrared light. Through is mechanism, light-activated protein inhibition was achieved through a Ruthenium(II)-Cobalt(II) bimetallic complex. PET occurs from a Ru(II) bipyridal complex to a covalently attached Co(III) complex and is gated by conformational changes that occur in tens of nanoseconds. Reduction of the Co(III)-sb by PET initiates displacement of the inert axial imidazole ligands, promoting coordination to active site histidines of alpha-thrombin. Upon exposure to 455 nm light, the rate of alpha-thrombin inhibition increases over five-fold upon irradiation. These results convey a strategy for light activation of inorganic therapeutic agents through PET utilizing redox-active metal centers.
520 $a In addition to the development of light-activated Co(III)-sb complexes, pancreatic tissue labeling was investigated through Gd(III)-dithiolane gold nanoparticle (AuNP) conjugates for magnetic resonance imaging. This facile functionalization strategy for AuNPs demonstrated significant increase Gd(III) particle loading and pancreas accumulation in C-57 mice. As a result, significant contrast image enhancement of the pancreas was achieved. These studies provide a nanomaterial platform that can be utilized for Gd(III) accumulation.
590 $a School code: 0163.
650 4 $a Inorganic chemistry. $3 3173556
650 4 $a Biochemistry. $3 518028
650 4 $a Analytical chemistry. $3 3168300
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710 2 $a Northwestern University. $b Chemistry. $3 1030729
773 0 $t Dissertation Abstracts International $g 76-10B(E).
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791 $a Ph.D.
792 $a 2015
793 $a English
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3705271