Abstract 2631

Most patients with acute myelogenous leukemia (AML) die from their disease. Although up to 75% of AML patients achieve remission after initial induction therapy, most of them will relapse and it has been proposed that relapse is the result of ineffective ablation of leukemia stem cells (LSCs) by chemotherapy. Elevated levels of phenotypically defined LSCs at diagnosis are predictive of minimal residual disease (MRD) which, in turn, predicts leukemic relapse, even after myeloablative stem cell transplantation. Therefore, in order to improve AML therapy, it is imperative to identify therapeutic strategies that effectively eliminate LSCs and we hypothesize that effective novel therapeutics in AML must be able to penetrate the protective environment of the BM niche. Thus, we investigated the use of nanotechnology as a “Trojan horse” to deliver anti-LSC drugs to the bone marrow niche. We have previously demonstrated that the plant derived compound parthenolide (PTL), which have sub-optimal bioavilability, can effectively ablate LSCs in vitro. We sought to encapsulate PTL in a novel multi-stage delivery vector system (MSV) comprised of two delivery carriers: (1) degradable porous silicon (pSi) and (2) nanoparticles containing drug of interest. To optimize specific delivery to the BM, we conjugated E-selectin thioaptamer ligand (ESTA-1) to the surface of the particles.

First, we performed feasibility studies of the system in AML-xenotransplanted mice. In order to demonstrate the delivery of MSV nanoparticles to the BM, we encapsulated Alexa Fluor 555-conjugated scramble-siRNA as a control. Nanoparticles were injected into established primary-AML xenotransplants. We found that 19.5% of the human cells from were positive for Alexa Fluor-555, thus demonstrating effective delivery to the BM of the xenotransplanted mice. Notably, we confirmed, using a single i.v. injection of MSV-PTL nanoparticles, that active PTL was delivered to the BM, were we observed a 4-fold decrease in viable human cells compared to controls.

To assess the in vivo efficacy of the MSV nanoparticles, established primary AML-xenotransplants were treated with either MSV-PTL, MSV-empty, PTL loaded micelles (third stage component only) or PBS. MSV-PTL treated mice demonstrated significantly decreased tumor burden (61.9 % human AML cells) compared to controls (75.8% PBS, 75.6% MSV-empty and 72.9 % micelle-PTL; p<0.05). To evaluate the anti-LSC activity of PTL, secondary transplants with equal numbers of human AML cells were performed. There was a 3.6 fold reduction in AML engraftment in the secondary xenotransplants for MSV-PTL treatment compared to MSV-empty controls (p<0.05), demonstrating that LSCs were targeted by MSV-PTL. Inhibition of NF-κB and activation of γH2AX, two intracellular events triggered specifically by PTL, were consistently identified in the human AML cells obtained from the BM of MSV-PTL treated mice.

Also, MSV-PTL enhanced ablation of AML cells not eliminated by ara-C in vivo. Secondary transplants further confirmed that treatment with MSV-PTL after ara-C treatment resulted in a significant decrease of engraftment of human AML cells, suggesting that PTL can eradicate ara-C-resistant LSCs.

Taken together, our data show that encapsulation of potent anti-LSC agents, such as PTL, into MSV effectively protects and delivers active drug to the BM of xenotransplanted mice and targets both AML blasts and LSCs. MSV-mediated drug delivery provides a novel method to deliver promising anti-LSC compounds, including those with poor bioavilability, to the BM niche, where they can act directly on LSCs.


No relevant conflicts of interest to declare.

Author notes


Asterisk with author names denotes non-ASH members.