Developing Targeted Drug Delivery Systems to Treat Leukemia

Project Collaborators: Rudi Fasan, Benjamin Frisch, Dr. Craig Jordan

Figure 1: A schematic of the development of bone marrow (BM) and LSC targeted drug delivery systems (DDS) for acute myeloid leukemia (AML). .

Acute myeloid leukemia (AML) recurrences are attributed to leukemia stem cells (LSCs) and a harsh marrow microenvironment that supports AML cell survival. LSCs in particular survive conventional chemotherapy and radiation treatments leading to relapse in patients. Drugs such as parthenolide (PTL) and micheliolide have has shown remarkable efficacy in inducing selective apoptosis in LSCs. However, these compounds’ low water solubility prevents them from reaching therapeutically effective levels in the blood stream. To circumvent this problem, we are developing a novel micelle delivery system to solubilize and target compounds.

The micelles are formed from diblock copolymers that are hydrophilic and hydrophobic. In physiologic solutions, the carriers self-assemble into spherical carriers with hydrophobic interiors that can be loaded with hydrophobic compounds. Thus, we hypothesize that these carriers will greatly increase compound blood concentrations, enhancing their chemotherapeutic efficacy. We also aim to conjugate peptides to the corona of the micelles to home to the bone microenvironment and the LSCs, reducing the overall physiologic burden of drug and to selectively ablate LSCs, reducing AML recurrence rates.

Figure 1 shows a schematic of the development of bone marrow (BM) and LSC targeted drug delivery systems (DDS) for acute myeloid leukemia (AML). Briefly, To maximize BM drug accumulation, a targeting peptide with specificity towards osteoclast deposited tartrate-resistant acid phosphatase (TRAP) was introduced to polymeric nanoparticles (NP) to rescue the bone marrow microenvironment (BMME) through c-chemokine ligand 3 (CCL3) disruption and LSC inhibition. The bone- targeted NP system is broadly applicable to bone and bone marrow associated diseases including multiple myeloma, bone regeneration, osteomyelitis, etc. Regardless of the system chosen, these studies show the potential of targeted DDS to increase tissue/cell-specific drug delivery and reduce off-target effects and toxicities associated with traditional treatment options.