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Development of Peptide-Conjugate Biomimics for Targeted Ti(IV)-Based Anticancer D

Award Number: SC1CA190504
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2014
PERIOD OF PERFORMANCE END DATE: 08/31/2019

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Development of Peptide-Conjugate Biomimics for Targeted Ti(IV)-Based Anticancer D - DESCRIPTION (provided by applicant): Titanium(IV) compounds are excellent anticancer drug candidates with a broad spectrum of effect. Formulation issues due to the solution instability of these compounds and the generation of inert Ti(IV) oxide species have hindered their transition to the drug market. Several biomolecules, namely the serum protein transferrin (Tf), circumvent this problem by providing stable coordination sites that enable Ti(IV) to be transported in the body. The proposal herein seeks to exploit the Tf metal binding site and its intracellular metal transport in the development of a biomimetic drug design strategy for Ti(IV)-based anticancer compounds. Novel ligands will be synthesized specific to facilitating the anticancer properties of Ti(IV) by containing two important structural components. One component is a bioactive peptide to enable selective and receptor-mediated transport into cancer cells. The bioactive peptides substance P (SP) and transferrin receptor 1 binding peptides are excellent candidates for the peptide component of the Ti(IV) ligands because their primary receptors are overexpressed in many cancer cells relative to normal cells. These receptors are not overexpressed in the same cancer cell lines and thus this study will show how bioactive peptides can be used to fine-tune targeting of select cancers. The peptide component will be conjugated to a Tf mimicking metal binding moiety with a metal coordination preference that can be manipulated for Ti(IV) release in cancer cells. The N,N'-di(o-hydroxybenzyl) ethylenediamine-N,N'-diacetic acid (HBED) and deferasirox metal binding ligands are suitable for this purpose. HBED binds Ti(IV) with a high affinity but binds Fe(III) with an even stronger affinity and the same is expected of deferasirox. The ligands have the potential to stably transport Ti(IV) into cells and then release Ti(IV) in exchange for Fe(III). By depleting cancer cells of Fe(III), which have a higher requirement for the metal ion, the ligands can work in synergism with Ti(IV) to trigger cell death. A series of cytotoxicity mechanistic studies of the Ti(IV) peptide-conjugate compounds will be performed to examine the contributions of the peptide, the metal binding moiety, and the Ti(IV) ion. The kinetics of Ti(IV) displacement by Fe(III) will be investigated to determine its physiological feasibility. Structure activity relatioship studies will be performed to elucidate the structural properties of both the peptide and metal binding moiety components that maximize the cytotoxicity of Ti(IV). In addition, insight into intracellular Ti(IV) target sites and metabolic pathways inhibited by Ti(IV) will be garnered through a combination of metallomics and metabolomics mass spectrometry studies. These mechanistic studies will afford optimization of the rationally designed Ti(IV) compounds.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2022 ( Subtotal = $4,682 )
2022	2017	UNIVERSITY OF PUERTO RICO	39 PONCE DE LEON AVE	SAN JUAN	PR	00931	SAN JUAN	USA	Biomedical Research and Research Training	000	4	9/26/2022	NON-COMPETING CONTINUATION	$4,682
														Subtotal = $4,682

Issue Date FY: 2020 ( Subtotal = -$10,982 )
2020	2017	UNIVERSITY OF PUERTO RICO	39 PONCE DE LEON AVE	SAN JUAN	PR	00931	SAN JUAN	USA	Biomedical Research and Research Training	000	4	4/10/2020	NON-COMPETING CONTINUATION	-$10,982
														Subtotal = -$10,982

Issue Date FY: 2017 ( Subtotal = $348,000 )
2017	2017	UNIVERSITY OF PUERTO RICO	39 PONCE DE LEON AVE	SAN JUAN	PR	00931	SAN JUAN	USA	Biomedical Research and Research Training	000	4	8/29/2017	NON-COMPETING CONTINUATION	$348,000
														Subtotal = $348,000

Issue Date FY: 2016 ( Subtotal = $348,000 )
2016	2016	UNIVERSITY OF PUERTO RICO, RIO PIEDRAS CAMPUS	PO BOX 21790	SAN JUAN	PR			USA	Biomedical Research and Research Training	000	3	8/4/2016	NON-COMPETING CONTINUATION	$348,000
														Subtotal = $348,000

Issue Date FY: 2015 ( Subtotal = $348,000 )
2015	2015	UNIVERSITY OF PUERTO RICO, RIO PIEDRAS CAMPUS	PO BOX 21790	SAN JUAN	PR			USA	Biomedical Research and Research Training	000	2	8/25/2015	NON-COMPETING CONTINUATION	$348,000
														Subtotal = $348,000

Issue Date FY: 2014 ( Subtotal = $348,000 )
2014	2014	UNIVERSITY OF PUERTO RICO, RIO PIEDRAS CAMPUS	PO BOX 21790	SAN JUAN	PR			USA	Biomedical Research and Research Training	000	1	8/18/2014	NEW	$348,000
														Subtotal = $348,000

Grand Total All Awards = $1,385,700

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Development of Peptide-Conjugate Biomimics for Targeted Ti(IV)-Based Anticancer D

Award Number: SC1CA190504

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/01/2014

PERIOD OF PERFORMANCE END DATE: 08/31/2019

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