Friday, November 22, 2024 11/22/2024

Stimuli-responsive mucin1-specific nanoparticles for efficacious combinatorial chemotherapy of pancreatic ductal adenocarcinoma

Award Number: R01CA263897
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Abstract Pancreatic ductal adenocarcinoma (PDAC) is an aggressive and devastating malignant disease of the exocrine pancreas which is characterized by invasiveness, early metastasis and profound resistance to therapies. PDAC is the fourth-leading cause of cancer-related mortality in the United States, with approximately 60,430 new cases and 48,220 deaths anticipated in 2021. Unfortunately, despite the tremendous scientific efforts, it is shocking to note that PDAC has the worst prognosis with 5-year survival rate of 10% which has not significantly improved from the past 40 years. Further, the PDAC burden is projected to increase in the next decade and is anticipated to be the second-leading cause of cancer-related deaths by 2030. The high mortality and awful prognosis of PDAC can be attributed to multifactorial reasons like its intrinsic and acquired resistant behavior, early micrometastatic dissemination, desmoplastic effect and heterogeneities in tumors, rendering the current treatments rather ineffective. Developing reliable methods for the effective treatment of PDAC will have a major impact on the clinical outcome for this deadly disease. We have designed, synthesized and characterized a target-specific, stimuli-responsive MSN platform for the controlled delivery of cisplatin (cisPt) and gemcitabine (Gem) (TAB004-Gem-cisPt-MSNs) with an optimal drug ratio. Our preliminary data demonstrates that this delivery system effectively targets tumor associated MUC1 (tMUC1), increases therapeutic efficiency with reduced toxicity in both a syngeneic and a spontaneous mouse model that overexpressed tMUC1. In this project, we are proposing to develop novel MSN-based sequential delivery systems for the effective treatment of PDAC. The hypothesis underlying this proposal is that by developing a sequential nanoparticle-based regimen where the primary nanoplatform targets the tumor stroma to deliver a SHh inhibitor; and the secondary nanocarrier, hTAB004-Gem-cisPt-MSNs, is used to release chemotherapeutics to PDAC cells, the treatment of PDAC will be dramatically improved. The main goal of this project will be accomplished by the completion of three Aims: 1) Study the effect of hTAB004-Gem-cisPt-MSNs on the biological stability of Gem and its mechanistic role on DNA damage repair in PDAC cells; 2) Investigate the pharmacokinetics, biodistribution and safety of CyP-MSNs and hTAB004-Gem-cisPt-MSNs; and the therapeutic efficacy of the sequential therapy in patient derived xenograft (PDX) mice; and 3) Evaluate the targeting, therapeutic efficacy and effectiveness against tumor metastasis of the sequential therapy CyP-MSNs and hTAB004-Gem-cisPt-MSNs in a transgenic spontaneous PDA.MUC1 mice model. This data will be the proof of concept for successful bench to bedside translation of this platform.


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 = $442,634 )
2024	2024	UNIVERSITY OF NORTH CAROLINA AT CHARLOTTE, THE	9201 UNIVERSITY CITY BLVD	CHARLOTTE	NC	28223	MECKLENBURG	USA	Cancer Treatment Research	000	3	7/24/2024	NON-COMPETING CONTINUATION	$442,634
														Subtotal = $442,634

Issue Date FY: 2023 ( Subtotal = $329,848 )
2023	2023	UNIVERSITY OF NORTH CAROLINA AT CHARLOTTE, THE	9201 UNIVERSITY CITY BLVD	CHARLOTTE	NC	28223	MECKLENBURG	USA	Cancer Treatment Research	000	2	8/8/2023	NON-COMPETING CONTINUATION	$329,848
														Subtotal = $329,848

Issue Date FY: 2022 ( Subtotal = $349,329 )
2022	2022	UNIVERSITY OF NORTH CAROLINA AT CHARLOTTE, THE	9201 UNIVERSITY CITY BLVD	CHARLOTTE	NC	28223	MECKLENBURG	USA	Cancer Treatment Research	000	1	6/28/2022	NEW	$349,329
														Subtotal = $349,329

Grand Total All Awards = $1,121,811

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Stimuli-responsive mucin1-specific nanoparticles for efficacious combinatorial chemotherapy of pancreatic ductal adenocarcinoma

Award Number: R01CA263897

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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