Targeting epigenetic pathway with gold nanoparticles for acute myeloid leukemia therapy
Abstract
Leukemia remains a fatal disease for most patients and novel therapeutic strategies are urgently needed. Aberrant DNA methylation is an epigenetic modification that is important in the initiation and progression of leukemia. Here, we demonstrated NCL/miR-221/NFκB/DNMT1 axis as a new molecular pathway promoting aggressive acute myeloid leukemia (AML) leukemogenesis and successfully designed and prepared a nuclear localization signal (NLS) peptide-targeted gold nanoparticles with co-loaded anti-221 and AS1411 (NPsN-AS1411/a221), which can specifically target NCL/miR-221/NFκB/DNMT1 signaling pathway in AML. NPsN-AS1411/a221 synergistically abrogate endogenous miR-221 promoting cancerous growth by inhibiting the expression of p27Kip1 suppressor gene, as well as effectively deregulate the DNMT1 expression through NFκB signaling which led to a reduction of global DNA methylation and the restoration of tumor suppressor p15INK4B via its promoter DNA hypomethylation. Functionally, NPsN-AS1411/a221 remarkably blockage leukemia proliferation and clonogenic potential in NCL/miR-221/NFκB/DNMT1 positive AML cell lines. More importantly, NPsN-AS1411/a221 cooperatively extend the overall survival, lower the white blood cells, reverse splenomegaly, inhibit blasts in bone marrow and metastatic to lung in a preclinical AML animal model. Altogether, our studies provide a proof of concept for multiple-functional drug delivery system that based on the specific gene network involved in tumor growth, and highlight the clinical potential of NCL/miR-221/NFκB/DNMT1-targeted AML nanotherapy.
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AS1411 has been systemically evaluated in a Phase II clinical trial for leukemia treatment.
“AS1411, a 26-mer DNA oligonucleotide, has been systemically evaluated in Phase II clinical trial for leukemia treatment.47”
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- Authors
- Deng, R., Shen, N., Yang, Y., Yu, H., Xu, S., Yang, Y.-W., Liu, S., Meguellati, K., & Yan, F.
- Affiliations
- Jilin University (CN)
- Chinese Academy of Sciences (CN)
- University of Minnesota (US)
- Corresponding author
- Meguellati, Kamel
- Yan, Fei
- Venue
- Biomaterials
- Publisher
- Elsevier BV
- Published
- 2018-06
- Volume
- 167
- Pages
- 80-90
- ISSN
- 0142-9612 (ISSN-L)
- OpenAlex
- W2790409421
- Cited by
- 106
- References
- 51
- Citations by year
- 2026: 3 · 2025: 7 · 2024: 12 · 2023: 13 · 2022: 19 · 2021: 19 · 2020: 15 · 2019: 14 · 2018: 4
- FWCI
- 9.31
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Biomaterials (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Jilin University, China (451170102027, 451170102020, 1G317L321461)
- Topics
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Keywords
- acute myeloid leukemia, gold nanoparticles, epigenetic therapy, DNA methylation, miR-221, NF-κB signaling, DNMT1, p27, CDKN2B, AS1411, targeted drug delivery, nanomedicine, leukemogenesis, lung metastasis
- MeSH terms
- Antagomirs, Animals, Drug Carriers, Gold, Humans, Male, Mice, Inbred C57BL, Oligodeoxyribonucleotides, Genetic Therapy, Leukemia, Myeloid, Acute, DNA Methylation, Nuclear Localization Signals, MicroRNAs, Epigenesis, Genetic, Cell Line, Tumor, Aptamers, Nucleotide, Metal Nanoparticles
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