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BIOLOGICAL FATE AND BIOCOMPATIBILITY OF SILICA-BASED NANOCONSTRUCTS

Award Number: R01ES024681
ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/28/2007
PERIOD OF PERFORMANCE END DATE: 11/30/2026

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BIOLOGICAL FATE AND BIOCOMPATIBILITY OF SILICA-BASED NANOCONSTRUCTS - PROJECT SUMMARY A major challenge with systemic administration of silica nanoparticles (SNPs) is clearance by and accumulation in organs of mononuclear phagocytic system (MPS), and subsequent immune response. Poor loading capacity of SNPs, their stability and vacuolization in macrophages, and potentially lower metabolism and clearance rates in patient populations may necessitate administration of high and frequent doses of SNPs which could lead to MPS saturation and overload. Detailed investigation of immunotoxicity of SNPs in the MPS is needed to establish their safety profile to choose drug carriers with well-defined immunological properties. The influence of SNPs on the fate and function of phagocytes after uptake and saturation, and on host immune response need further elucidation. The correlation between the physicochemical properties of SNPs and the mechanisms of sex-dependent toxicity is unclear. Also, the immune response alteration upon i.v. administration of SNPs and the mechanisms behind this response are largely unknown. To address these knowledge gaps in this grant application the following Specific Aims are proposed: 1) To investigate the influence of saturation of macrophages with SNPs on their phagocytic activity, survival, proliferation, and immune signaling as a function of nanoparticle physicochemical properties. The underlying hypothesis to be tested in this aim is that saturation of macrophages by SNPs will influence their normal function, molecular signaling, and fate based on nanoparticle characteristics. 2) To investigate bone marrow toxicity and function of tissue-resident macrophages after i.v. administration of SNPs, and assess the number and activation status of circulating phagocytes after in vitro exposure to SNPs. The underlying hypothesis to be tested in this aim is that size, geometry, and porosity of SNPs influence the normal function of bone marrow, tissue-resident macrophages, and peripheral blood phagocytes, a phenomenon which may be reversible and depend on dose and frequency of administration. 3) To investigate the immune side effects and anti-PEG response of systemically administered SNPs as a function of animal sex and particle physicochemical properties. The underlying hypotheses are: i) Anti-PEG IgM and IgG will be generated in a time-dependent manner upon exposure to PEGylated SNPs; ii) variation in immune response in female vs male Th1 and Th2 bias animal models will contribute to SNP toxicity and immune- mediated side effects. This proposal is significant because understanding key physicochemical properties of SNPs with well- defined immunological properties will help establish safer platforms for intravenous drug delivery. It is innovative because for the first time it approaches different SNP interactions with various components of the immune system as a result of animal-sex and different immune-biased in a systematic fashion.


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 = $461,025 )
2025	2025	UNIVERSITY OF UTAH	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Environmental Health	000	14	11/15/2024	NON-COMPETING CONTINUATION	$461,025
														Subtotal = $461,025

Issue Date FY: 2024 ( Subtotal = $485,659 )
2024	2024	UNIVERSITY OF UTAH	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Environmental Health	000	13	12/1/2023	NON-COMPETING CONTINUATION	$485,659
														Subtotal = $485,659

Issue Date FY: 2023 ( Subtotal = $501,303 )
2023	2023	UNIVERSITY OF UTAH, THE	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Environmental Health	000	12	11/23/2022	NON-COMPETING CONTINUATION	$501,303
														Subtotal = $501,303

Issue Date FY: 2022 ( Subtotal = $480,633 )
2022	2022	UNIVERSITY OF UTAH, THE	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Environmental Health	000	11	2/25/2022	COMPETING CONTINUATION	$480,633
														Subtotal = $480,633

Issue Date FY: 2021 ( Subtotal = -$11,302 )
2021	2018	UNIVERSITY OF UTAH, THE	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Environmental Health	000	10	5/30/2021	NON-COMPETING CONTINUATION	-$11,302
														Subtotal = -$11,302

Issue Date FY: 2018 ( Subtotal = $335,250 )
2018	2018	UNIVERSITY OF UTAH, THE	201 S PRESIDENT CIRCLE RM 408	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Environmental Health	000	10	5/28/2018	NON-COMPETING CONTINUATION	$335,250
														Subtotal = $335,250

Issue Date FY: 2017 ( Subtotal = $335,250 )
2017	2017	UNIVERSITY OF UTAH, THE	201 S PRESIDENT CIRCLE RM 408	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Environmental Health	000	9	5/25/2017	NON-COMPETING CONTINUATION	$335,250
														Subtotal = $335,250

Issue Date FY: 2016 ( Subtotal = $335,250 )
2016	2016	UNIVERSITY OF UTAH	201 SOUTH PRESIDENT`S CIRCLE	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Environmental Health	000	8	6/3/2016	NON-COMPETING CONTINUATION	$335,250
														Subtotal = $335,250

Issue Date FY: 2015 ( Subtotal = $335,250 )
2015	2015	UNIVERSITY OF UTAH	201 SOUTH PRESIDENT`S CIRCLE	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Environmental Health	000	7	5/12/2015	NON-COMPETING CONTINUATION	$335,250
														Subtotal = $335,250

Issue Date FY: 2014 ( Subtotal = $335,250 )
2014	2014	UNIVERSITY OF UTAH	201 SOUTH PRESIDENT`S CIRCLE	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Environmental Health	000	6	8/28/2014	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$335,250
														Subtotal = $335,250

Grand Total All Awards = $3,593,568

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BIOLOGICAL FATE AND BIOCOMPATIBILITY OF SILICA-BASED NANOCONSTRUCTS

Award Number: R01ES024681

ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/28/2007

PERIOD OF PERFORMANCE END DATE: 11/30/2026

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