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Sub-100 nm and scalable self-therapeutic nanoparticles to target autophagy in pancreatic cancer

Award Number: R43CA272110
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/08/2022
PERIOD OF PERFORMANCE END DATE: 02/28/2025

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Sub-100 nm and scalable self-therapeutic nanoparticles to target autophagy in pancreatic cancer - Title: Sub-100 nm and scalable self-therapeutic nanoparticles to target autophagy in pancreatic cancer Project Summary The 5-year survival rate of pancreatic ductal adenocarcinoma (PDAC) is less than 10% and the lack of effective treatment is one of the major impediments for the clinical management of PDAC. Pancreatic cancer stem-like cells (PCSCs) have been linked to tumor metastasis, drug resistance, and aggressive behaviors and the enrichment of PCSC after chemotherapy is associated with more aggressive tumor rebound. Autophagy is the process of “self-digestion” and it is especially needed for the rapid proliferation in cancer cells. PDAC cells, particularly PCSCs, highly rely on elevated autophagy. Therefore, autophagy is a promising target in PDAC to improve treatment and overcome chemoresistance. Autophagy inhibition with aminoquinoline drugs, such as chloroquine (CQ) or hydroxychloroquine (HCQ), have been tested in several clinical trials including PDAC patients. Promisingly, an initial clinical benefit was observed when combined with chemotherapeutic drugs, such as gemcitabine and Abraxane in neoadjuvant setting. However, CQ/HCQ have limited potency for autophagy inhibition and potential side effects, and the concentrations of CQ/HCQ required to inhibit autophagy are not consistently achievable in the clinic due to the lack of a specific delivery approach. The overall goal of this SBIR phase I application is to develop sub-100 nm and scalable self-therapeutic nanoparticles as next-generation autophagy inhibitors to improve PDAC treatment in preclinical animal models, providing validation regarding the feasibility for Phase II studies that will eventually lead to an IND filing to FDA. Recently, we have developed an Autophagy inhibitor Self-delivered Nanodrug (AiSN) that offers superior potency for autophagy inhibition and specific drug delivery to improve PDAC treatment to HCQ. AiSN is a self-therapeutic nanoparticle that contains pure bisaminoquinoline (BAQ) derivative itself as the building block which has outstanding autophagy inhibiting- and lysosomal disrupting- capabilities. AiSN is 30x more effective than CQ and HCQ in vitro, and effectively kills PCSCs. As a self-delivered nanoparticle without a carrier, AiSN can efficiently accumulate at the PDAC tumor sites and effectively inhibit autophagy in PDAC animal models. AiSN successfully prevented tumorigenesis in PCSC-derived animal models and demonstrated superior anti-cancer efficacy in both PDAC- and PCSC-derived xenograft models as both a monotherapy and a combination therapy. These results were recently published in Nature Communications and built a strong foundation for this Phase I application, in which we plan to 1) develop a microfluidic approach for optimization of the AiSN formulation (smaller size, better stability and reproducibility) to further enhance its tumor penetration and support future large scale-production, and 2) investigate the pharmacokinetics, tumor penetration, and anti-cancer efficacy of the microfluidic assisted manufacturing AiSN in animal models. The successful completion of the proposed research will make the AiSN ready for next step of IND-enabling studies seeking IND approval. The proposed AiSN with greatly enhanced potency and specific delivery properties will significantly improve the efficacy and minimize the toxicity in the treatment of PDAC.


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 = $0 )
2025	2022	THERANOSTEC INC	5416 BRANINBURG CT	CARMICHAEL	CA	95608	SACRAMENTO	USA	Cancer Treatment Research	000	1	3/21/2025	NEW	$0
2025	2022	THERANOSTEC INC	5416 BRANINBURG CT	CARMICHAEL	CA	95608	SACRAMENTO	USA	Cancer Treatment Research	001	1	6/17/2025	NEW	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $399,999 )
2022	2022	THERANOSTEC INC	9944 NESTLING CIR	ELK GROVE	CA	95757	SACRAMENTO	USA	Cancer Treatment Research	000	1	9/8/2022	NEW	$399,999
														Subtotal = $399,999

Grand Total All Awards = $399,999

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Sub-100 nm and scalable self-therapeutic nanoparticles to target autophagy in pancreatic cancer

Award Number: R43CA272110

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/08/2022

PERIOD OF PERFORMANCE END DATE: 02/28/2025

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