Developing Targeted Drug Delivery Systems to Treat Leukemia
Rudi Fasan, Benjamin Frisch, Dr. Craig Jordan (University of Colorado)
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 (Figure 1).
Figure 1 (above): The overall outline of the AML project. A: Diblock polymers of different sizes containing various ratios of hydrophilic to hydrophobic portions are synthesized. B: Water is injected into the polymer solution to form micelles. Compounds are loaded into the micelles and high performance liquid chromatography is used to characterize the loading and release of the drug. C: Peptides selected for their affinity to the marrow microenvironment are conjugated to the micelle. D: In vitro testing ensures that the compounds are delivered to LSCs.
The micelles are formed from diblock copolymers that are hydrophilic and hydrophobic. In physiologic solutions, the carriers self-assemble (Figure 1) 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.
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