Monday, May 19, 2025 5/19/2025

A “STICK” theranostic nanoplatform for image-guided drug delivery to brain malignancies

Award Number: R01EB033677
ORGANIZATION: NATIONAL INSTITUTE Of BIOMEDICAL IMAGING & BIOENGINEERING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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A “STICK” theranostic nanoplatform for image-guided drug delivery to brain malignancies - Title: A “STICK” theranostic nanoplatform for image-guided drug delivery to brain malignancies Project Summary/Abstract Our long-term goal is to engineer a new and generalizable drug delivery platform to improve the delivery of various payloads to a series of brain malignancies and neurological disorders. The payloads can be imaging agents, chemotherapeutics, molecularly targeted drugs and immunotherapeutics. We identified the following major barriers for successful treatment of brain malignancies: 1) the blood-brain barrier/blood-brain tumor barrier (BBB/BBTB), 2) severe destabilizing effect in blood circulation that leads to a poor central nervous system (CNS) pharmacokinetics (PK) and 3) inability for agents to penetrate tumor tissue, and 4) lack of specificity for tumor cell delivery; resulting in poor treatment efficacy and off-target toxicity. To this end, we propose an integrated approach to mitigate these physiological barriers and mediate drug delivery to ensure disease targeting specificity. The goal of this revised R01 renewal application is to develop a new Sequential Targeting In CrosslinKing (STICK) nano-delivery platform to improve the drug delivery to brain malignancies. The characteristics of the proposed STICK nanoparticle (STICK NP) allow it to overcome the multiple barriers to penetrate deeply in brain malignancies. In Aim1, we will engineer new STICK NPs by designing new types of boronate crosslinkages to improve their CNS PK to maximize the time window to enhance the glucose transporter (GLUT1)-mediated transcytosis across the BBB/BBTB. The new crosslinkages also enhance the pH-responsive size transformation for improved tumor tissue penetration and sialic acid-targeting selectivity for enhanced tumor cell specificity. Our previous R01 grant focused on low grade brain tumors and as a logical but distinctive extension in this research topic, the target of our current project is diffuse midline glioma (DMG, previously called Diffuse Intrinsic Pontine Glioma (DIPG)), a high grade and the most aggressive form of pediatric glioma. DMG is the second most common type of primary, high grade brain tumor occurring in children with a median survival <1 year from diagnosis and the five-year survival rate of DMG is only around 2%. Discovery of the characteristic Histone 3-Lysine- 27-Methionine (H3K27M) mutation offers opportunity for development of targeted epigenetic therapies for this deadly disease. In Aim2, we will quantitatively determine the spatiotemporal distribution of the newly engineered STICK NPs in orthotopic DMG patient-derived xenograft (PDX) models and elucidate their delivery mechanisms by optical imaging, magnetic resonance imaging, liquid chromatography-mass spectrometry (LC- MS), and a series of biophysical approaches. In Aim3, two promising epigenetic drugs (panobinostat and ONC201) will be specifically delivered to DMG by encapsulations within selected STICK NPs for epigenetic therapy. The efficacy, toxicity, and molecular responses in tumor microenvironment will be investigated in orthotopic PDX models and genetically engineered murine (GEM) DMG models. This project has the great potential to significantly improve the clinical outcomes of DMG treatment. This concept can also be applied to improve the treatment of many other brain malignancies such as glioblastoma and brain metastases.


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 = $615,825 )
2025	2025	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR STE 300	DAVIS	CA	95618	YOLO	USA	Discovery and Applied Research for Technological Innovations to Improve Human Health	000	9	4/22/2025	NON-COMPETING CONTINUATION	$615,825
														Subtotal = $615,825

Issue Date FY: 2024 ( Subtotal = $603,509 )
2024	2024	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR STE 300	DAVIS	CA	95618	YOLO	USA	Discovery and Applied Research for Technological Innovations to Improve Human Health	000	8	7/16/2024	NON-COMPETING CONTINUATION	$603,509
														Subtotal = $603,509

Issue Date FY: 2023 ( Subtotal = $611,998 )
2023	2023	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	Discovery and Applied Research for Technological Innovations to Improve Human Health	000	7	6/8/2023	NON-COMPETING CONTINUATION	$611,998
														Subtotal = $611,998

Issue Date FY: 2022 ( Subtotal = $610,088 )
2022	2022	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	Discovery and Applied Research for Technological Innovations to Improve Human Health	000	6	8/14/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$610,088
														Subtotal = $610,088

Grand Total All Awards = $2,441,420

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A “STICK” theranostic nanoplatform for image-guided drug delivery to brain malignancies

Award Number: R01EB033677

ORGANIZATION: NATIONAL INSTITUTE Of BIOMEDICAL IMAGING & BIOENGINEERING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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