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Targeted Delivery of MicroRNAs by Nanoparticles: A Novel Therapeutic Strategy in Acute Myeloid Leukemia

Huang, Xiaomeng
http://orcid.org/0000-0001-9651-7503
http://rave.ohiolink.edu/etdc/view?acc_num=osu1405095496

Abstract Details

2014, Doctor of Philosophy, Ohio State University, Molecular, Cellular and Developmental Biology.
Acute myeloid leukemia (AML) is a biologically complex neoplastic disease of the hematopoietic system, characterized by an uncontrolled proliferation of malignant myeloid precursors leading to bone marrow failure at the clinical level. Today, the majority of AML patients fail to achieve long-term survival. Thus, new therapeutic approaches are needed. MicroRNAs (miRs), short noncoding RNAs that regulate the expression of their target mRNA-encoded proteins, are involved in tumorigenesis. We demonstrated that deregulated miR-29b and miR-181a in AML patients were associated with worse outcome. Moreover, AML patients with a higher pre-treatment level of miR-29b respond better to a hypomethylating agent, decitabine; and patients with higher miR-181a have longer survival under cytarabine/daunorubicine-based chemotherapy. Thus, increasing the levels of these miRs prior to the respective treatments may be beneficial. However, free synthetic miRs are easily degraded in the bio-fluid and have limited cellular uptake. To overcome this problem and explore miR-based therapy, our research focused on three major aims: (1) to develop a novel nanocarrier suitable for delivering miRs into AML cells; (2) to deliver miR-29b and assess the antileukemic activity; and (3) to investigate the role of miR-181a in AML, unravel the mechanism, and perform therapeutic evaluation via nanocarrier-delivered miR-181a. For aim 1, since AML cells overexpress transferrin receptor on their surface, we formulated novel transferrin (Tf) targeted anionic lipid based nanoparticles (NP) encapsulating miR mimic and demonstrated low toxicity and high efficiency. For aim 2, following miR-29b-nanoparticle treatment, we showed a significant increase in intracellular miR-29b levels and downregulation of its known targets. This resulted in decreased leukemia growth and improved survival in an AML mouse model. Furthermore, we showed that pretreatment with miR-29b nanoparticles improved the antileukemic activity of decitabine. For aim 3, we demonstrated that miR-181a served as a tumour suppressor in AML, which may be partially attributed to miR-181a supressing the oncogenic RAS/MAPK pathway by directly targeting RAS and MAPK1 proteins. We are the first to show that miR-181a-nanoparticle treatment leads to RAS/MAPK signaling inhibition and antileukemic activity. In conclusion, nanoparticle-based miR replacement therapy, particularly when combined with existing chemotherapy regimens, may represent a promising new treatment strategy for AML patients.
L. James Lee (Advisor)
Guido Marcucci (Advisor)
Robert Lee (Committee Member)
Natarajan Muthusamy (Committee Member)
216 p.
Biomedical Engineering; Cellular Biology; Molecular Biology
Acute Myeloid Leukemia, Nanoparticles, MicroRNA, Ras, Decitabine, Drug delivery

Recommended Citations

Citations

  • Huang, X. (2014). Targeted Delivery of MicroRNAs by Nanoparticles: A Novel Therapeutic Strategy in Acute Myeloid Leukemia [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1405095496

    APA Style (7th edition)

  • Huang, Xiaomeng. Targeted Delivery of MicroRNAs by Nanoparticles: A Novel Therapeutic Strategy in Acute Myeloid Leukemia . 2014. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1405095496.

    MLA Style (8th edition)

  • Huang, Xiaomeng. "Targeted Delivery of MicroRNAs by Nanoparticles: A Novel Therapeutic Strategy in Acute Myeloid Leukemia ." Doctoral dissertation, Ohio State University, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=osu1405095496

    Chicago Manual of Style (17th edition)

osu1405095496
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© 2014, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.