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bioRxiv · 10.1101/250985

HDL-AuNPs-BMS nanoparticle conjugates as molecularly targeted therapy for leukemia

Shen, N.·Yan, F.·Pang, J.·Gao, Z.·Al-Kali, A.·Haynes, C. L.·Litzow, M. R.·Liu, S.
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Abstract

In previous work, gold nanoparticles (AuNPs) with adsorbed high-density lipoprotein (HDL) nanoparticles have been utilized to deliver oligonucleotides, yet HDL-AuNPs functionalized with small molecule inhibitors have not been systematically explored. Here, we report an AuNP-based therapeutic system (HDL-AuNPs-BMS) for acute myeloid leukemia (AML) by delivering BMS309403 (BMS), a small molecule that selectively inhibits AML-promoting factor fatty acid binding protein 4 (FABP4). HDL-AuNPs-BMS are synthesized using a gold nanoparticle as template to control conjugate size and ensure a spherical shape to engineer HDL-like nanoparticle containing BMS. The zeta potential and size of the HDL-AuNPs obtained from transmission electron microscopy (TEM) show that the nanoparticles are electrostatically stable and 25 nm in diameter. Functionally, compared to free drug, HDL-AuNPs-BMS conjugates are more readily internalized by AML cells and have more pronounced effect on downregulation of DNA methyltransferase 1 (DNMT1), reduction of global DNA methylation, and restoration of epigenetically-silenced tumor suppressor p15INK4b coupled with AML growth arrest. Importantly, systemic administration of HDL-AuNPs-BMS conjugates into AML-bearing mice inhibits DNMT1-dependent DNA methylation, induces AML cell differentiation and diminishes AML disease progression without obvious side effects. In summary, these data, for the first time, demonstrate HDL-AuNPs as an effective delivery platform with great potential to attach distinct inhibitors, and HDL-AuNPs-BMS conjugates as a promising therapeutic platform to treat leukemia.

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Shen, N., Yan, F., Pang, J., Gao, Z., Al-Kali, A., Haynes, C. L., Litzow, M. R., Liu, S.. 2018-01-20. HDL-AuNPs-BMS nanoparticle conjugates as molecularly targeted therapy for leukemia. https://doi.org/10.1101/250985

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