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Development of multifunctional drug and immune modulator delivery nanoparticles for the treatment of cancer patients with comorbid atherosclerosis

Award Number: R01CA257861
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Project Summary Cancer and cardiovascular disease are leading causes of death in the United States. Given the high percentage of cancer patients with co-existing atherosclerosis, the development of cancer therapeutics that prevent progression of atherosclerosis have the potential to align cancer therapy goals with favorable cardiovascular outcomes. Hyaluronic acid (HA) has unique properties that are desirable for the development of biocompatible and biodegradable nanoparticle drug delivery systems for both cancer and atherosclerosis. We have developed a hyaluronic acid nanoparticle (HANP) conjugated with PD1 memetic peptides that target and block immune checkpoint protein PD-L1 and carry the cholesterol-lowering drug Avasimibe (PD1Y-HANP/Ava). Avasimibe is a multifunctional agent that decreases cholesterol accumulation, inhibits tumor cell growth, and enhances immune response by activating cytotoxic T cells. We found that systemic administrations of PD1Y-HANP/Ava led to targeted delivery into tumors and atherosclerotic plaques, inhibition of tumor growth and atherosclerosis progression, and significant improvement in mouse survival in a dual mouse cancer and atherosclerosis model. In this study, we hypothesize that systemic delivery of urokinase plasminogen activator receptor (uPAR), PD- L1 and CD44 co-targeted HANP carrying Avasimibe (ATF/PD1Y-HANP/Ava) leads to the efficient delivery of the HANP/Ava into tumors and atherosclerotic plaques, resulting in a significant anti-tumor growth effect by direct inhibition of tumor cell proliferation, activation of cytotoxic CD8+ T cells, and pro-immune modulatory effect of ATF/PD1Y-HANP/Ava in tumor microenvironment. We further hypothesize that delivery of targeted PD1Y- HANP/Ava into atherosclerotic plaques decreases cholesterol-rich macrophages and infiltrating immune cells, and thereby prevents atherosclerosis progression. To develop and validate the proposed immunotherapy, we will first develop ATF/PD1Y-HANP/Ava and examine the efficiency of targeted delivery in metastatic mouse colon cancer models (Aim 1). Therapeutic efficacy and immune responses following targeted PD1Y-HANP/Ava treatment, alone or in combination with a chemotherapy drug, irinotecan, will be evaluated in the mouse cancer models (Aim 1). We will then determine the effect of the targeted PD1Y-HANP/Ava on targeted delivery, immune responses and therapeutic efficacy in tumor and atherosclerotic plaques in a dual mouse colon cancer and atherosclerosis model (Aim 2). Immunological analysis of tumors and atherosclerotic plaques will allow us to determine therapy-related changes in immune cell types and functions, especially CD8+ T cell activity. We will then investigate the feasibility of translation in cancer patients by examining targeted delivery and direct cytotoxic effect of the targeted PD1Y-HANP/Ava in colon cancer patient derived xenograft models (Aim 3). Finally, pharmacokinetics, toxicity, biodistribution and systemic immune responses will be determined in mice (Aim 4). Results of this research should provide us with preclinical data for translational development of a phase 1 clinical trial using this novel targeted immunotherapy for metastatic colon cancer patients with comorbid atherosclerosis.


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: 2024 ( Subtotal = $149,521 )
2024	2024	EMORY UNIVERSITY	201 DOWMAN DR	ATLANTA	GA	30322	DEKALB	USA	Cancer Treatment Research	000	4	1/26/2024	NON-COMPETING CONTINUATION	$122,366
2024	2024	EMORY UNIVERSITY	201 DOWMAN DR NE	ATLANTA	GA	30322	DEKALB	USA	Cancer Treatment Research	001	4	4/17/2024	NON-COMPETING CONTINUATION	$27,155
														Subtotal = $149,521

Issue Date FY: 2023 ( Subtotal = $532,237 )
2023	2023	EMORY UNIVERSITY	201 DOWMAN DR	ATLANTA	GA	30322	DEKALB	USA	Cancer Treatment Research	000	3	1/25/2023	NON-COMPETING CONTINUATION	$532,237
														Subtotal = $532,237

Issue Date FY: 2022 ( Subtotal = $532,237 )
2022	2022	EMORY UNIVERSITY	201 DOWMAN DR	ATLANTA	GA	30322	DEKALB	USA	Cancer Treatment Research	001	2	4/26/2022	NON-COMPETING CONTINUATION	$43,449
2022	2022	EMORY UNIVERSITY	201 DOWMAN DR	ATLANTA	GA	30322	DEKALB	USA	Cancer Treatment Research	000	2	1/7/2022	NON-COMPETING CONTINUATION	$488,788
														Subtotal = $532,237

Issue Date FY: 2021 ( Subtotal = $542,085 )
2021	2021	EMORY UNIVERSITY	201 DOWMAN DR	ATLANTA	GA	30322	DEKALB	USA	Cancer Treatment Research	000	1	1/26/2021	NEW	$542,085
														Subtotal = $542,085

Grand Total All Awards = $1,756,080

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Development of multifunctional drug and immune modulator delivery nanoparticles for the treatment of cancer patients with comorbid atherosclerosis

Award Number: R01CA257861

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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