# Nanoparticle mediated microenvironmental targeting of CCL3 signaling for the treatment of acute myelogenous leukemia

> **NIH NIH F31** · UNIVERSITY OF ROCHESTER · 2020 · $21,080

## Abstract

For over 30 years, the acute myelogenous leukemia (AML) survival rate has been stagnant at 27% despite
extensive research and development of new treatments. Interactions between AML blasts and the bone
marrow microenvironment contribute to treatment resistance. Specifically, AML cells secrete C-chemokine (C-
C motif) ligand 3 (CCL3) which signals through C-C chemokine receptor type 5 (CCR5) to reduce the number
and function of mature osteoblasts in the marrow. Reduction in osteoblast number and inhibition of osteoblast
function contributes to AML blast survival and leads to loss of normal hematopoiesis in the marrow. Blocking
CCL3 signaling using the inhibitor, Maraviroc (MVC) serves as a novel strategy to restore osteoblast function
and prime the marrow for subsequent therapies to ablate leukemic cells. Due to rapid metabolism and
clearance of small molecule drugs upon systemic administration, achieving therapeutically relevant doses of
MVC in the bone marrow niche is challenging. In fact, our preliminary studies using free MVC indicated no
reduction of leukemia burden in the marrow. Here, we propose a novel marrow targeting nanoparticle (NP)
approach to deliver MVC to inhibit CCL3 signaling. Remarkably, poly(styrene-alt-maleic anhydride)-
poly(styrene) based micelle nanoparticles (PSMA-b-PS NPs) functionalized with tartrate resistant-acid
phosphatase (TRAP) binding peptide (TBP) preferentially accumulate in the marrow at 2-fold higher levels than
untargeted NP controls. TBP-NPMVC treatment reduces leukemic burden in the marrow, which is not observed
with free MVC treatment. While this preliminary data is promising, the therapeutic outcomes can be improved
by enhancing the marrow targeting selectivity and minimizing off-target accumulation of TBP-NPs. We will test
the hypothesis that NPs designed to maximize marrow selectivity will enhance MVC-mediated CCL3
inhibition within bone marrow and restore osteoblast function and normal hematopoiesis. To test this
hypothesis, we will first focus on enhancing the marrow accumulation of TBP-NPs in Aim 1. We will do so by
controlling TBP spatial presentation, incorporating a spacer, and varying the peptide density on our NPs (Aim
1A). In Aim 1B, we will assess in vitro binding affinity and in vivo marrow accumulation versus off-target
organs of TBP-NP designs. In Aim 2, we will assess the biodistribution of TBP-NPs on BCR-ABL/Nup98-
HoxA9 bcCML and MLL/AF9 mouse models (Aim 2A) and determine the effect of MVC delivery on restoring
osteolineage cells and reducing AML burden in the marrow (Aim 2B). At the completion of this project we
expect to identify a new strategy for priming the bone marrow using our versatile NPs, an approach that can be
leveraged for other drugs and marrow associated cancers and diseases.

## Key facts

- **NIH application ID:** 9868285
- **Project number:** 5F31CA228391-03
- **Recipient organization:** UNIVERSITY OF ROCHESTER
- **Principal Investigator:** Marian Adriana Ackun-Farmmer
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $21,080
- **Award type:** 5
- **Project period:** 2018-04-01 → 2020-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9868285

## Citation

> US National Institutes of Health, RePORTER application 9868285, Nanoparticle mediated microenvironmental targeting of CCL3 signaling for the treatment of acute myelogenous leukemia (5F31CA228391-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9868285. Licensed CC0.

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