Developing Targeted Drug Delivery Systems to Treat Leukemia
Acute myeloid leukemia (AML) recurrences are attributed to leukemia stem cells (LSCs that are capable of surviving conventional chemotherapy and radiation treatments. The drug parthenolide (PTL) has shown remarkable efficacy in inducing selective apoptosis in LSCs. However, PTL's low water solubility prevents it 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 PTL (Figure 1). We undertake this endevor in collaboration with an AML specialist from the University of Rochester Medical Center.
Figure 1: The overall outline of the parthenolide delivery 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. Parthenolide is loaded into the micelles and high performance liquid chromatography is used to characterize the loading and release of the drug. C: Antibodies selected for their specificity towards LSCs are conjugated to the micelle. The antibodies target one of the antigens expressed only by LSCs. D: In vitro testing ensures that that the parthenolide is 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 PTL. Thus, we hypothesize that these carriers will greatly increase PTL blood concentrations, enhancing its chemotherapeutic efficacy. We also aim to conjugate antibodies to the corona of the micelles to home directly to LSCs, reducing the overall physiologic burden of drug to selectively ablate LSCs, reducing AML recurrence rates.