# Self-immolative prodrug/miRNA nanoparticle combinations for cancer treatment

> **NIH NIH R01** · UNIVERSITY OF NEBRASKA MEDICAL CENTER · 2020 · $456,624

## Abstract

The goal of this proposal is to improve systemic therapies of colon cancer using self-assembled nanomaterials
that can deliver potent anticancer miRNA and then degrade in cancer cells to active small molecule modulators
of dysregulated polyamine metabolism. Despite tremendous therapeutic potential, clinical translation of miRNA
faces major unsolved pharmaceutical delivery challenges. Due to the involvement of multiple mutations in 
tumorigenesis and tumor progression, combination of miRNAs with modulators of polyamine metabolism has 
significant therapeutic potential. The fact that polyamine metabolism is downstream from many oncogenes and
tumor suppressor pathways make it a logical target for such combination miRNA therapy approaches. Our 
objective is to develop polyamine prodrugs (PaPs) that can modulate dysregulated polyamine metabolism and
encapsulate and systemically deliver anticancer miR-34a. The hypothesis is that self-immolative PaPs based on
modulators of polyamine metabolism will deliver miR-34a to the tumors, which will result in enhanced 
combination effect due to the downregulation of tumor polyamine biosynthesis and upregulation of polyamine catabolism
and restoration of important cell growth and death-regulatory functions due to miR-34a. We will accomplish the
objectives in three specific aims: (1) we will optimize formulation of tumor-penetrating PaP/miR-34a 
nanoparticles that deliver miRNA and modulate polyamine metabolism. Based on encouraging anticancer in vivo activity
in our preliminary studies, we hypothesize that particle modification with tumor-penetrating iRGD peptide and
with stabilizing superhydrophobic fluorinated moieties will result in efficient systemic delivery. (2) we will 
determine the mechanism of action of PaP/miR-34a nanoparticles in vitro. Our results indicate that PaPs are effective
in reducing tumor cell growth and induction of apoptosis, but the precise mechanism of action of the 
nanoparticles and how it relates to their intracellular trafficking, disassembly and rate of polyamine analog release is
unknown. We will ascertain the mechanisms of action and determine which composition strategies are most
effective in producing strong antitumor effect. (3) we will test the in vivo efficacy of the particles in colon cancer
using human tumor xenografts and syngeneic immune competent tumor models. We will conduct comprehensive
evaluation of anticancer activity and survival advantage of PaP/miR-34a in models relevant for human disease.
Contribution of the antitumor immunogenicity to the efficacy will be also studied due to known effects of 
polyamine analogs on increasing the antitumor immune response. We predict that we will be able to prepare 
nanoparticles with improved anticancer activity and prolonged survival. The proposed integrative approach is innovative
because of the dual-function design of the PaP polymers as modulators of polyamine metabolism and miRNA
carriers. The research is significant because...

## Key facts

- **NIH application ID:** 9869874
- **Project number:** 5R01CA235863-02
- **Recipient organization:** UNIVERSITY OF NEBRASKA MEDICAL CENTER
- **Principal Investigator:** Robert A. Casero
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $456,624
- **Award type:** 5
- **Project period:** 2019-02-11 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9869874

## Citation

> US National Institutes of Health, RePORTER application 9869874, Self-immolative prodrug/miRNA nanoparticle combinations for cancer treatment (5R01CA235863-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9869874. Licensed CC0.

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