1. Lipid–Albumin Nanoparticles (LAN) for Therapeutic Delivery of Antisense Oligonucleotide against HIF-1α
- Author
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Bryant C. Yung, Hong Li, Young Bok Lee, Deog Joong Kim, Robert J. Lee, Jishan Quan, Yang Liu, Xinwei Cheng, Mengzi Zhang, and Chang-Ho Ahn
- Subjects
0301 basic medicine ,Blotting, Western ,Oligonucleotides ,Mice, Nude ,Pharmaceutical Science ,Alpha (ethology) ,02 engineering and technology ,Biology ,Endocytosis ,Mice ,03 medical and health sciences ,Hypoxia-Inducible Factor 1-Alpha ,Downregulation and upregulation ,Albumins ,Cell Line, Tumor ,Drug Discovery ,Animals ,Humans ,Cytotoxicity ,Drug Carriers ,Reverse Transcriptase Polymerase Chain Reaction ,Oligonucleotide ,Pinocytosis ,Oligonucleotides, Antisense ,Hypoxia-Inducible Factor 1, alpha Subunit ,021001 nanoscience & nanotechnology ,Lipids ,Xenograft Model Antitumor Assays ,Molecular biology ,030104 developmental biology ,Nanoparticles ,Molecular Medicine ,0210 nano-technology ,HeLa Cells ,Conjugate - Abstract
Lipid-albumin nanoparticles (LAN) were synthesized for delivery of RX-0047, an antisense oligonucleotide (ASO) against the hypoxia inducible factor-1 alpha (HIF-1α) to solid tumor. These lipid nanoparticles (LNs) incorporated a human serum albumin-pentaethylenehexamine (HSA-PEHA) conjugate, which is cationic and can form electrostatic complexes with negatively charged oligonucleotides. The delivery efficiency of LAN-RX-0047 was investigated in KB cells and a KB murine xenograft model. When KB cells were treated with LAN-RX-0047, significant HIF-1α downregulation and enhanced cellular uptake were observed compared to LN-RX-0047. LN-RX-0047 and LAN-RX-0047 showed similar cytotoxicity against KB cells with IC50 values of 19.3 ± 3.8 and 20.1 ± 4.2 μM, respectively. LAN-RX-0047 was shown to be taken up by the cells via the macropinocytosis and caveolae-mediated endocytosis pathways while LN-RX-0047 was taken up by cells via caveolae-mediated endocytosis. In the KB xenograft tumor model, LAN-RX-0047 exhibited tumor suppressive activity and significantly reduced intratumoral HIF-1α expression compared to LN-RX-0047. Furthermore, LAN-RX-0047 greatly increased survival time of mice bearing KB-1 xenograft tumors at doses of either 3 mg/kg or 16 mg/kg. These results indicated that LAN-RX-0047 is a highly effective vehicle for therapeutic delivery of antisense agents to tumor.
- Published
- 2016