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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-NANO-M (01))
Program Officer
Yovandich, Jason L
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Ohio State University
Other Health Professions
Schools of Pharmacy
United States
Zip Code
Huang, Xiaomeng; Schwind, Sebastian; Santhanam, Ramasamy et al. (2016) Targeting the RAS/MAPK pathway with miR-181a in acute myeloid leukemia. Oncotarget 7:59273-59286
Kanthamneni, Naveen; Yung, Bryant; Lee, Robert J (2016) Effect of Eudragit on In Vitro Transfection Efficiency of PEI-DNA Complexes. Anticancer Res 36:81-5
Li, Hong; Xu, Songlin; Quan, Jishan et al. (2015) CD33-Targeted Lipid Nanoparticles (aCD33LNs) for Therapeutic Delivery of GTI-2040 to Acute Myelogenous Leukemia. Mol Pharm 12:2010-8
Yang, Shuang; Yang, Xuewei; Liu, Yan et al. (2015) Non-covalent complexes of folic acid and oleic acid conjugated polyethylenimine: An efficient vehicle for antisense oligonucleotide delivery. Colloids Surf B Biointerfaces 135:274-82
Mao, Yicheng; Wang, Jiang; Zhao, Yuan et al. (2014) A novel liposomal formulation of FTY720 (fingolimod) for promising enhanced targeted delivery. Nanomedicine 10:393-400
Paecharoenchai, Orapan; Teng, Lesheng; Yung, Bryant C et al. (2013) Nonionic surfactant vesicles for delivery of RNAi therapeutics. Nanomedicine (Lond) 8:1865-73
Huang, Xiaomeng; Schwind, Sebastian; Yu, Bo et al. (2013) Targeted delivery of microRNA-29b by transferrin-conjugated anionic lipopolyplex nanoparticles: a novel therapeutic strategy in acute myeloid leukemia. Clin Cancer Res 19:2355-67
Baskar, Sivasubramanian; Muthusamy, Natarajan (2013) Antibody-based therapeutics for the treatment of human B cell malignancies. Curr Allergy Asthma Rep 13:33-43
Xie, Jing; Teng, Lesheng; Yang, Zhaogang et al. (2013) A polyethylenimine-linoleic acid conjugate for antisense oligonucleotide delivery. Biomed Res Int 2013:710502
Piao, Longzhu; Li, Hong; Teng, Lesheng et al. (2013) Human serum albumin-coated lipid nanoparticles for delivery of siRNA to breast cancer. Nanomedicine 9:122-9

Showing the most recent 10 out of 33 publications