# Mesenchymal Stem Cell-Based Targeted Combined Therapy for Pancreatic Ductal Adenocarcinoma

> **NIH NIH P20** · NORTH DAKOTA STATE UNIVERSITY · 2022 · $205,857

## Abstract

PROJECT SUMMARY
 Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal human malignancies, with a five-year
survival rate of 10.8%. Lack of efficient strategies to achieve cytotoxic concentrations of chemotherapeutics in
the tumor tissue and the tumor's innate resistance to chemotherapy are the significant barriers in improving
treatment outcomes for PDAC. Thus, new approaches for tumor-selective delivery of chemotherapeutics can
enhance the therapeutic efficacy while minimizing chemotherapy-associated toxicities. Unfortunately, current
nanocarrier systems primarily rely on the inefficient passive accumulation in the tumor. Here we propose a new
approach for treating PDAC with a combination of a novel histone deacetylase (HDAC) inhibitor, entinostat, and
a leading chemotherapeutic agent, oxaliplatin, at their synergistic ratio. The proposed studies will evaluate
nanoengineered MSC as a drug delivery platform to selectively accumulate cytotoxic agents in pancreatic
tumors. Based on the existing literature and our preliminary findings, we hypothesize that MSCs-mediated tumor-
targeted delivery of oxaliplatin and entinostat at their synergistic ratio would significantly reduce pancreatic tumor
growth and enhance the efficacy without acute toxicity. To test our hypothesis, we propose the following Aims.
Aim 1: Formulate drug-loaded nano-MSCs and determine their cellular efficacy. Our preliminary studies
demonstrate a dose-dependent synergistic therapeutic interaction between free oxaliplatin and entinostat in an
in vitro model of PDAC. We will encapsulate oxaliplatin and entinostat separately in the surface-functionalized
polymeric nanoparticles. Nanoparticles will be characterized for their particle size, surface charge, drug loading,
and in vitro drug release. The time- and dose-dependent drug loading capacity of MSCs and drug release rate
and mechanism from nanoengineered MSCs will also be evaluated. Also, both nanoparticle formulation and
nanoengineering protocols will be optimized to improve the drug loading capacity of MSCs without affecting their
native phenotype, viability, or migratory behavior. Finally, we will determine the synergistic ratio of entinostat and
oxaliplatin-loaded MSCs to kill PDAC cells. Based on our preliminary results, the working hypothesis for this Aim
is that the nanoengineered MSCs will enable sustained release of oxaliplatin without introducing resistance,
ensuring enhanced tumor cell killing.
Aim 2: Evaluate the effectiveness of nano-MSCs using an orthotopic mouse model of PDAC. First, we will
determine the maximum tolerated dose (MTD), pharmacokinetics, biodistribution, acute and subchronic toxicities
of nanoengineered MSCs in an orthotopic mouse model of PDAC. Using this optimized dosing strategy, we will
determine the therapeutic efficacy of oxaliplatin-loaded nanoengineered MSCs alone and combined with
entinostat-loaded MSCs using an orthotopic mouse model of PDAC. We will conduct detailed histopathol...

## Key facts

- **NIH application ID:** 10496133
- **Project number:** 2P20GM109024-06
- **Recipient organization:** NORTH DAKOTA STATE UNIVERSITY
- **Principal Investigator:** Buddhadev Layek
- **Activity code:** P20 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $205,857
- **Award type:** 2
- **Project period:** 2016-03-01 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10496133

## Citation

> US National Institutes of Health, RePORTER application 10496133, Mesenchymal Stem Cell-Based Targeted Combined Therapy for Pancreatic Ductal Adenocarcinoma (2P20GM109024-06). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10496133. Licensed CC0.

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