The goal of this project is to develop nanotherapeutics that can specifically deliver the chemotherapeutic drug daunorubicin into acute myeloid leukemia (AML) stem cells (targeted delivery) and release the drug inside the cells (timed release) in order to eradicate this cell population. Current chemotherapy for AML is disappointing in that it can cure only a minority of AML patients and is associated with severe toxicity and significant mortality even with intensive inpatient monitoring and supportive care. Leukemia stem cells (LSC) are relatively resistant to the conventional chemotherapy and can subsequently produce more leukemia cells to cause disease recurrence. In order to cure leukemia, LSC must be eradicated. The C-type lectin-like molecule-1 (CLL-1) is a cell surface protein that is specifically expressed on most AML LSC, but not on normal hematopoietic stem cells. We have developed a peptide that specifically targets CLL1. When this peptide is covalently attached to a nanometer-scale micellar drug formulation, the resulted targeting nanoparticles, called micelles, can specifically deliver the drug load into cells expressing CLL1, including clinical leukemia specimens. The drug-loaded, CLL1-targeting micelles are stable in blood, and can potentially improve therapy against AML by (1) delivering a high local concentration of daunorubicin specifically into LSC, overwhelming the resistant mechanisms and eradicating LSC; (2) killing leukemic cells throughout the body with the release of daunorubicin from the micelles and LSC into circulation; (3) decreasing therapy-induced toxicity and mortality owing to the sequestration of the drug inside the micelles; and (4) allowing administration of high-dose daunorubicin with reduced toxicity through formulation of daunorubicin into micelles.
This project aims to develop nanometer-scale micelles loaded with a chemotherapeutic drug daunorubicin that can specifically deliver the drug load into leukemia stem cells and eradicate this cell population, while also being able to kill leukemia cell throughout the body and decrease therapy-related toxicity.
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