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Encapsulation and delayed release of gemcitabine by aluminum metal-organic frameworks

Award Number: SC3GM136647
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/01/2020
PERIOD OF PERFORMANCE END DATE: 04/30/2025

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Encapsulation and delayed release of gemcitabine by aluminum metal-organic frameworks - PROJECT SUMMARY This proposal seeks to study encapsulation of gemcitabine to complexes with aluminum metal-organic frameworks (Al-MOFs), mechanism of bonding, chemical kinetics of delayed release, and cytotoxicity to pancreatic cancer and healthy cells. Standard chemotherapy of solid tumors is systemic (oral or intravenous). Gemcitabine is FDA-approved pyrimidine drug to treat pancreatic cancer. Systemic administration shows “burst” effect with quick increase of drug concentration, which leads to severe side effects. Systemic chemotherapy often uses large amount of drug (grams), which is undesirable for prolonged treatments. Alternative administration is by local delayed release with drug-eluting implant. The only FDA-approved anticancer implant is Gliadel wafer, where polymer matrix holds small amount (mg) of carmustine for prolonged release. Common encapsulation matrices are polymers and vesicles, which form weak bonds with drug molecules, and a moderately slow release. Metal-organic frameworks (MOFs) emerged as promising matrix for drug encapsulation and delayed release. Recently, PI of this SC-3 proposal published book on interactions of MOFs with small molecules. MOFs contain organic linkers and metal cations. Certain MOFs show stronger bonds with drug molecules and slower release than other matrices. Mainly, nano-MOFs and chemically unstable solid MOFs with substantial toxicity were studied for drug release. Al-MOFs are water-insoluble, structurally versatile, have porosity and high stability, and low toxicity. The overall goal of this project is to study selected Al-MOFs as new matrix for encapsulation and prolonged release of gemcitabine. Our goals are to study fundamental chemical properties of complexes of gemcitabine with Al-MOFs, kinetics of delayed release, and cytotoxicity. The goals will be accomplished by the following specific Aims. Aim I. Synthesize complexes of gemcitabine with Al-MOFs which contain archetypal linkers, and determine bonding mechanism. Each Al-MOF has archetypal linker with or without (hetero)aromatic group as binding site. We will determine structure of complexes, and mechanism of bonding of encapsulated gemcitabine to groups in Al-MOFs by the complementary methods of instrumental analysis. Aim II. Study kinetics of time-delayed release of gemcitabine to buffer solution. We will establish the relationships between kinetic parameters of release, bonding mechanism, and structure of archetypal linkers. Aim III. Study short- and long-term in-vitro cytotoxicity of complexes to pancreatic cancer and healthy cells. We will draw conclusions how numeric parameters of the time-dependent cytotoxicity are related to bonding mechanism in complexes. This research will determine the connections between bonding mechanism, kinetic release parameters, and time-dependent cytotoxicity. In summary, this study will reveal Al-MOFs as new promising materials for prolonged local chemotherapy of pancreatic cancer.


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: 2025 ( Subtotal = -$176 )
2025	2022	MORGAN STATE UNIVERSITY	1700 E COLD SPRING LN	BALTIMORE	MD	21251	BALTIMORE CITY	USA	Biomedical Research and Research Training	000	3	9/10/2025	NON-COMPETING CONTINUATION	-$176
														Subtotal = -$176

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2022	MORGAN STATE UNIVERSITY	1700 E COLD SPRING LN	BALTIMORE	MD	21251	BALTIMORE CITY	USA	Biomedical Research and Research Training	000	3	5/9/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $113,250 )
2022	2022	MORGAN STATE UNIVERSITY	1700 E COLD SPRING LN	BALTIMORE	MD	21251	BALTIMORE CITY	USA	Biomedical Research and Research Training	000	3	5/12/2022	NON-COMPETING CONTINUATION	$113,250
														Subtotal = $113,250

Issue Date FY: 2021 ( Subtotal = $113,250 )
2021	2021	MORGAN STATE UNIVERSITY	1700 E COLD SPRING LN	BALTIMORE	MD	21251	BALTIMORE CITY	USA	Biomedical Research and Research Training	004	2	9/17/2021	NON-COMPETING CONTINUATION	$113,250
2021	2021	MORGAN STATE UNIVERSITY	1700 E COLD SPRING LN	BALTIMORE	MD	21251	BALTIMORE CITY	USA	Biomedical Research and Research Training	003	2	8/26/2021	NON-COMPETING CONTINUATION	-$113,250
2021	2021	MORGAN STATE UNIVERSITY	1700 E COLD SPRING LN	BALTIMORE	MD	21251	BALTIMORE CITY	USA	Biomedical Research and Research Training	000	2	4/21/2021	NON-COMPETING CONTINUATION	$113,250
2021	2020	MORGAN STATE UNIVERSITY	1700 E COLD SPRING LN	BALTIMORE	MD	21251	BALTIMORE CITY	USA	Biomedical Research and Research Training	001	1	7/29/2021	NEW	-$99,628
2021	2020	MORGAN STATE UNIVERSITY	1700 E COLD SPRING LN	BALTIMORE	MD	21251	BALTIMORE CITY	USA	Biomedical Research and Research Training	002	1	7/30/2021	NEW	$99,628
														Subtotal = $113,250

Issue Date FY: 2020 ( Subtotal = $99,628 )
2020	2020	MORGAN STATE UNIVERSITY	1700 E COLD SPRING LN	BALTIMORE	MD	21251	BALTIMORE CITY	USA	Biomedical Research and Research Training	000	1	4/17/2020	NEW	$99,628
														Subtotal = $99,628

Grand Total All Awards = $325,952

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Encapsulation and delayed release of gemcitabine by aluminum metal-organic frameworks

Award Number: SC3GM136647

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/01/2020

PERIOD OF PERFORMANCE END DATE: 04/30/2025

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