# Stroma penetrating and immune modulating nanoparticles for image-guided therapy of pancreatic cancer

> **NIH NIH R01** · EMORY UNIVERSITY · 2023 · $28,146

## Abstract

Project Summary
Recent advances in targeted delivery of nanoparticle/drugs and CAR T cell therapy have shown promises in the
development of novel approaches for overcoming resistance to chemo- and immunotherapy in pancreatic cancer.
A major obstacle in CAR T therapy in pancreatic cancer is the presence of multiple barriers that prevent cytotoxic
T cells reaching tumors and actively killing tumor cells. Dense tumor stromal cells and extracellular matrix create
physical and biological barriers to trap T cells in the stroma and inhibit T cell function. There is an unmet need
of effective approaches to improve delivery of CAR T cells in pancreatic cancer. Tumor targeted, stroma-
penetrating theranostic iron oxide nanoparticles (IONPs) developed in the parent R01 project offer an opportunity
to develop a combination therapy to improve targeted delivery and intratumoral distribution of CAR T cells and
overall therapeutic responses. Our results showed that uPAR-targeted and stroma breaking ligand (ATFmmp14)
can overcome stromal cellular and extracellular matrix barriers to enhance tumor delivery of nanoparticle-drugs
and T cells in human pancreatic PDX and transgenic mouse tumor models. In this supplement research project,
we hypothesize that the binding of uPAR targeted, stroma-penetrating IONPs carrying chemo- and
immunotherapeutic agents to CAR T cells significantly enhances delivery of CAR T cells and chemotherapy
drugs into pancreatic cancer. Immune checkpoint PD-L1 and CTLA4 blocking peptides conjugated on the IONPs
further activate CAR T cell function. Those combined effects lead to a strong therapeutic response in pancreatic
cancer and overcome therapy resistance. In the proposed study, we will first determine the effect of ATFmmp14-
conjugated IONPs carrying a chemotherapy agent, SN38, on viability and cytotoxicity of anti-MUC16 and/or
Mesothelin CAR T cells in vitro in human pancreatic cancer cell lines. Therapeutic effect of co-delivery of the
targeted IONP/SN38 with CAR T cells will be evaluated in a pancreatic cancer PDX model in SCID mice (Aim
1). Next, we will develop a novel targeted and stroma-penetrating CAR T cell delivery system by backpacking
with ATFmmp14-IONP/SN38 carrying PD-L1 and/or CTLA4 blocking peptides, mediated by a CXCR4 inhibitor
(BL-8040), for overcoming resistance to chemo- and CAR T cell therapy in pancreatic cancer (Aim 2). The effect
on targeted delivery of CAR T cells and therapeutic efficacy using the backpack system containing ATFmmp14-
IONP/SN38/immune checkpoint inhibitors will be evaluated in the pancreatic cancer PDX model (Aim 2). We
will then investigate the therapeutic effects of the targeted chemo- and immunotherapy IONP-CAR T cells on
tumor cells, immune cells and tumor stroma immune microenvironment using a mouse anti-MUC16 CAR T cells
in a transgenic mouse pancreatic cancer cell line derived mouse tumor model (Aim 2). Finally, the feasibility of
MR imaging for tracking intratumoral delivery of targeted...

## Key facts

- **NIH application ID:** 10747717
- **Project number:** 3R01CA261251-02S1
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Hui Mao
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $28,146
- **Award type:** 3
- **Project period:** 2023-03-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10747717

## Citation

> US National Institutes of Health, RePORTER application 10747717, Stroma penetrating and immune modulating nanoparticles for image-guided therapy of pancreatic cancer (3R01CA261251-02S1). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10747717. Licensed CC0.

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