Targeted drug delivery has the potential to improve the efficacy of a therapeutic agent while reducing its side effects. Folate receptor type-beta (FRB) is a cell surface marker selectively expressed by approximately70 percent of acute myeloid leukemias (AMLs). Increased FR-beta expression can be specifically induced by all trans retinoic acid (ATRA) in FR-beta-positive KG-1 and primary AML cells, without inducing cellular differentiation or growth inhibition. Folic acid is a high affinity ligand for FR-beta (Kd approximately 1 nM). Importantly, FR-beta expressed by normal hematopoietic cells has been found to be non-functional, whereas the receptor expressed by KG-1 AML cells and FR-beta-transfected CHO cells mediates selective uptake and cytotoxicity of folate-coated liposomes. Both uptake and cytotoxicity of folate coated liposome doxorubicin (f-L-Dox) in KG-1 cells were further increased by ATRA, which induced FR-beta upregulation. Moreover, f-L-DOX exhibited greater therapeutic efficacy than non-targeted liposomal DOX (LDox) in FR positive murine L1210JF and human KG-1 AML ascitic tumor models. Increased survival due to treatment with f-L-Dox was further enhanced by ATRA in the KG-1 engrafted mice. FR-targeted liposomal Dox delivery has also been shown to bypass the P-glycoprotein-mediated drug efflux in FR positive tumor cells exhibiting resistance to free Dox. The objective of this project is to evaluate f-L-Dox, combined with ATRA-induction of FR-beta upregulation, for the treatment of AML, a concept based on the selective targeting of the FR positive tumor cells.
The specific aims are: 1. To evaluate the effect of ATRA on FR-beta expression by AML cells in vivo. 2. To evaluate liposome formulation and FR-beta level as factors in the binding and in vitro cytotoxicity of f-L-Dox to AML cells, as well as the pharmacokinetic properties of the liposomes; the effect of dietary folate will also be studied. 3. To evaluate the selective cytotoxicity of f-L-Dox, alone or combined with ATRA, against AML blast cells, clonogenic progenitor cells (CFUs), and primitive AML stem cells (SL-Ics); and 4. To evaluate the in vivo therapeutic efficacy of f-L-Dox alone or combined with ATRA in murine leukemia models. This project should lead to the development of a novel therapeutic strategy based on the combination of targeted drug delivery to tumor cells and upregulation of the cellular target for the treatment of chemotherapy refractory AMLs.
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