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Formulation of a targeted nanoparticle system for the treatment of chemoresistant breast cancer

Award Number: SC3GM142001
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: 09/01/2021
PERIOD OF PERFORMANCE END DATE: 06/30/2025

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Formulation of a targeted nanoparticle system for the treatment of chemoresistant breast cancer - ABSTRACT The development of multidrug resistance (MDR) in cancer cells is of grave concern, limiting the efficacy of anticancer agents and, hence, the failure of breast cancer therapy. Clinical research and application revealed that in spite of its potential anticancer effects, doxorubicin is highly toxic, and its long-term application may cause dose-dependent irreversible cardiomyopathy, severe cardiac toxicity, or liver damage, thereby limiting its application in breast cancer treatment. Even if the drug is super-efficient, if it still causes off-target toxicity and damages non-cancerous cells and tissues, the drug wouldn’t be a great remedy to treat that particular disease. As such, the greater potential of using doxorubicin as anticancer therapeutic depends on the availability of a targeted delivery vehicle, which will not only enhance the killing of cancer cells but also minimize the off-target toxicity to non-cancerous cells. The goal of this study is to enhance the delivery of doxorubicin by formulating an aptamer-labeled liposomal nanoparticle delivery system that will carry and deliver doxorubicin specifically into chemoresistant Her-2+ breast cancer cells. We have recently reported that down regulating nuclear expression of MDR1 P-gp (ABCB1 gene) by P-gp specific siRNA could increase the delivery of doxorubicin to doxorubicin resistant breast cancer cells. However, since the Dox was delivered as a free drug solution without encapsulating it into a particle for targeted delivery, it still caused toxicity to other non-cancerous cells. The targeted delivery of siRNA to knockdown multi-drug resistant genes such as MDR1 P-gp, MRP or BCRP might be helpful to circumvent MDR using the apt-labeled formulations that we have developed in our lab, however, there are some questions that still need to be addressed (1) how can we deliver doxorubicin in a more targeted fashion to the chemoresistant breast cancer cells so that the drug-enhanced cytotoxicity to cancer cells increases with a minimal toxicity to the non-cancerous cells? We assume that a targeted delivery system is an utmost requirement whether it is delivering siRNA to silence chemoresistant genes or an actual chemodrug which will kill cancer cells without killing non- cancerous cells. To address the chemoresistance as well as off-target toxicity, a targeted delivery system for doxorubicin needs to be developed which should be innovative, comparable and can minimize the toxicity to other non-cancerous cells. And (2) a strategy needs to be in place to determine whether the targeted nanoparticles will carry both doxorubicin and siRNA within the same particles or in different particles to get the best results preventing chemoresistance and limiting off- target toxicity. Our hypothesis is that delivering doxorubicin and MDR-silencing siRNAs separately by targeted nanoparticle system will enhance the cellular toxicity and antitumor effects as compared to a targeted nanoparticle system that delivers the drug and siRNA simultaneously. This hypothesis will be tested through two specific aims: Aim 1: Targeted delivery of doxorubicin liposomes for Her-2 positive breast cancer treatment. Aim 2: Assess whether the targeted nanoparticles will carry both doxorubicin and siRNA within the same particles or in different particles to get the best results preventing chemoresistance and limiting off-target toxicity.


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: 2026 ( Subtotal = -$903 )
2026	2024	XAVIER UNIVERSITY OF LOUISIANA	1 DREXEL DR	NEW ORLEANS	LA	70125	ORLEANS	USA	Biomedical Research and Research Training	000	4	3/12/2026	NON-COMPETING CONTINUATION	-$903
														Subtotal = -$903

Issue Date FY: 2024 ( Subtotal = $112,500 )
2024	2024	XAVIER UNIVERSITY OF LOUISIANA	1 DREXEL DR	NEW ORLEANS	LA	70125	ORLEANS	USA	Biomedical Research and Research Training	000	4	6/26/2024	NON-COMPETING CONTINUATION	$112,500
														Subtotal = $112,500

Issue Date FY: 2023 ( Subtotal = $112,500 )
2023	2023	XAVIER UNIVERSITY OF LOUISIANA	1 DREXEL DR	NEW ORLEANS	LA	70125	ORLEANS	USA	Biomedical Research and Research Training	000	3	6/14/2023	NON-COMPETING CONTINUATION	$112,500
														Subtotal = $112,500

Issue Date FY: 2022 ( Subtotal = $112,500 )
2022	2022	XAVIER UNIVERSITY OF LOUISIANA	1 DREXEL DR	NEW ORLEANS	LA	70125	ORLEANS	USA	Biomedical Research and Research Training	000	2	6/13/2022	NON-COMPETING CONTINUATION	$112,500
														Subtotal = $112,500

Issue Date FY: 2021 ( Subtotal = $111,000 )
2021	2021	XAVIER UNIVERSITY OF LOUISIANA	1 DREXEL DR	NEW ORLEANS	LA	70125	ORLEANS	USA	Biomedical Research and Research Training	000	1	8/20/2021	NEW	$111,000
														Subtotal = $111,000

Grand Total All Awards = $447,597

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Formulation of a targeted nanoparticle system for the treatment of chemoresistant breast cancer

Award Number: SC3GM142001

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: 09/01/2021

PERIOD OF PERFORMANCE END DATE: 06/30/2025

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