Acute myeloid leukemia (AML) is the most common type of leukemia in adults and the second most common in children. While progress has been made in the treatment of several types of leukemia, improvement in survival rate for both adult and pediatric AML has not occurred. Development of targeted nanocarriers loaded with molecularly targeted therapeutics represents a novel strategy for improving treatment of AML. GTI-2040, an antisense oligodeoxyribonucleotide (ODN) against the R2 subunit of ribonucleotide reductase (RNR), is a promising agent for overcoming chemoresistance in AML. Enhancement in clinical efficacy of GTI-2040 and reduction in side effects can potentially be achieved through targeted delivery of GTI-2040 using multifunctional nanovehicles consisting of immunoconjugates of lipopolyplexes (ILPs). The objective of this project, therefore, is to design, synthesize, and evaluate anti-CD33 mAb conjugated lipopolyplexes (anti- CD33-ILPs) for down regulation of R2 and for AML therapy. CD33 is a myeloid lineage marker frequently expressed on AML blast cells. ILPs will be synthesized by both conventional bulk-mixing (BM) and novel micro-/nanofluidic (MF/NF) methods, and conjugated to anti-CD33 via a protein a linker. This will be followed by in vitro evaluation for R2 down regulation activity and in vivo evaluation for pharmacokinetic (PK) properties, pharmacodynamic (PD) endpoints and therapeutic activities.
The Specific Aims of this application include to 1) design and optimize anti-CD33-ILP formulation for targeted delivery of GTI-2040 to AML cells;2) develop micro-/nanofluidic (MF/NF) methods for synthesis of anti-CD33-GTI-2040-ILPs;3) evaluate in vitro the biological activities of anti-CD33-GTI- 2040-ILPs using AML cell lines and patients'primary malignant blasts;4) evaluate pharmacokinetic (PK) properties and pharmacodynamic (PD) endpoints and therapeutic activities of anti-CD33-GTI- 2040-ILPs in preclinical murine models of AML. This project will be carried out via an interdisciplinary approach by investigators with expertise in drug delivery (RLee), PK/PD (Chan), nanoengineering (LJLee, Guan), biochemistry and molecular biology (Jin), and experimental therapeutics (Marcucci, Byrd, Muthusamy). Success of this project may lead to not only development of a novel clinical agent for AML, but also technological advances in nanocarrier design and synthesis with broad applications in oligonucleotide therapeutics.
We seek to develop novel nanotechnology to create multifunctional immunonanoparticles for the delivery antisense oligodeoxyribonucleotides to treat acute myeloid leukemia (AML). Success of this project may lead to not only development of a novel clinical agent for AML, but also technological advances in nanocarrier design and synthesis with broad applications in oligonucleotide therapeutics.
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