# Prodrugs targeting norepinephrine transporter for dual-selective therapy of refractory neuroblastoma

> **NIH NIH R01** · CHILDREN'S HOSP OF PHILADELPHIA · 2020 · $622,966

## Abstract

Abstract
This project focuses on the design and evaluation of prodrugs with dual pharmacological selectivity,
combining molecularly targeted mode of action with a tissue-specific, active uptake process (uptake-1)
to enhance drug delivery to aggressive neuroendrocrine neoplasms, including high-risk neuroblastoma
(NB) – the deadliest extracranial pediatric solid tumor currently lacking effective treatment options.
Norepinephrine transporter (NET) driving accumulation of norepinephrine and its functional analogs is
expressed by most solid tumors developing from sympathoadrenal precursor cells. However, tumor
radiotherapy targeted to NET has shown limited efficiency, while causing serious adverse effects due to
significant off-target distribution and extensive damage to healthy tissues. Centered on a dual-selective
experimental drug delivery strategy integrating the uptake-1 process with a replication-dependent mode
of drug action to confine the pharmacological effect to proliferative tumor cells expressing NET, this
project aims to evaluate and optimize a pharmacotherapeutic approach designed to effectively combat
refractory disease not responding to existing treatments, while minimizing toxicity to healthy organs and
tissues. In our proof-of-concept experiments, a tripartite prodrug design integrating NET affinity with
unique molecular targeting of a potent and selective topoisomerase I inhibitor was shown to be
essential for achieving sustained intratumoral drug presence and markedly extended survival in
clinically relevant models of aggressive neuroblastoma. Guided by these results, we hypothesize that
dual-selective pharmacotherapy using NET-targeted prodrugs can provide a selective, safe and
efficient way of treating different forms of high-risk disease. We also hypothesize that potency and
selectivity of this approach will be enhanced by combining it with clinically proven small-molecule
agents modulating tissue-specific expression of NET. These hypotheses will be tested by pursuing the
following specific aims: Aim 1 studies will focus on comparative evaluation of polymeric carrier-linked
prodrug constructs with regard to their cell uptake and growth inhibitory effects on primary NB cells and
cell lines with different phenotypes, as a function of their molecular design and the potentiating action of
the NET expression enhancing agents; Aim 2 and Aim 3 studies will comparatively evaluate the
biodistribution profiles and therapeutic effectiveness of a series of tripartite prodrugs, with the goal to
identify and optimize key construction variables, to establish feasibility of pharmacologically modulating
NET expression for improving drug delivery and treatment outcomes, and to examine the roles of tumor
phenotype and disease status in clinically relevant models of aggressive NB. The proposed research
focusing on NET-targeted prodrugs equipped with dual pharmacological selectivity is significant by
informing the development of a new strategy for t...

## Key facts

- **NIH application ID:** 10033345
- **Project number:** 1R01CA251883-01
- **Recipient organization:** CHILDREN'S HOSP OF PHILADELPHIA
- **Principal Investigator:** GARRETT M BRODEUR
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $622,966
- **Award type:** 1
- **Project period:** 2020-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10033345

## Citation

> US National Institutes of Health, RePORTER application 10033345, Prodrugs targeting norepinephrine transporter for dual-selective therapy of refractory neuroblastoma (1R01CA251883-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10033345. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*