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 1 B, 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.
Acute myeloid leukemia (AML) is a public health concern that kills 2% of children and 70% of adults over the age of 65 diagnosed worldwide. This project is taking an unprecedented approach of treating AML by using a drug delivery approach to prime the bone marrow so that AML is less likely to evade standard chemotherapy. The proposed plan is expected to improve AML survival and will lead to development of a novel, versatile marrow-targeted approach that is applicable for other types of leukemia and marrow associated diseases.
