Lipid-Albumin Nanoparticles (LAN) for Therapeutic Delivery of Antisense Oligonucleotide against HIF-1α.

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.

• Authors: Hong Li, Jishan Quan, Mengzi Zhang, Bryant C Yung, Xinwei Cheng, Yang Liu, Young B Lee, Chang-Ho Ahn, Deog Joong Kim, Robert J Lee
• Journal: Molecular pharmaceutics (Mol Pharm) Vol. 13 Issue 7 Pg. 2555-62 (07 05 2016) ISSN: 1543-8392 [Electronic] United States
• PMID: 27253378 (Publication Type: Journal Article)

Chemical References

• Albumins
• Drug Carriers
• Hypoxia-Inducible Factor 1, alpha Subunit
• Lipids
• Oligonucleotides
• Oligonucleotides, Antisense
• RX 0047

Topics

• Albumins
• Animals
• Blotting, Western
• Cell Line, Tumor
• Drug Carriers (administration & dosage, chemistry)
• HeLa Cells
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (antagonists & inhibitors, metabolism)
• Lipids (chemistry)
• Mice
• Mice, Nude
• Nanoparticles (chemistry)
• Oligonucleotides (chemistry, therapeutic use)
• Oligonucleotides, Antisense (chemistry)
• Reverse Transcriptase Polymerase Chain Reaction
• Xenograft Model Antitumor Assays